ABSTRACT
Diabetes is a methabolic disease characterized by hyperglycemia, with high morbidity and mortility worldwide. Diabetic microvasular complications, which are considered as an important group of hyperglycemia imperfections, caused by increased endothelial permeability and can progress to severe impairments in several organs. Although diabetic nephropathy, neuropathy and retinopathy are the most common microvascular complications of hyperglycemia, it also affects choroid plexus. Here we briefly reviewed the characteristic and etiology of these complications emphasizing on cerebrospinal fluid.
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DOI: 10.3923/jbs.2010.411.423
URL: https://scialert.net/abstract/?doi=jbs.2010.411.423
INTRODUCTION
Diabetes Mellitus (DM) is a heterogeneous group of metabolic disease in which the body does not produce and/or utilize insulin (Alberti and Zimmet, 1998; Keecia et al., 2005; Abi-Chahin et al., 2009). Diabetes is going to become pandemic in the 21st century and its global prevalence is predicted to increase to more than 4% by 2030 (Wild et al., 2004).
Among the diabetes imperfections, microvascular complications are common in patients with type1 and type 2 diabetes and represent significant sources of morbidity and mortality (Schwarzenberg et al., 2007; Abi-Chahin et al., 2009).
Five risk factors that play important roles in the development of microvascular disease are hyperglycemia, individual susceptibility (Gerrits et al., 2008; Tarnow et al., 1998), hypertension (UK Prospective Diabetes Study Group, 1998), hyperlipidemia and obesity (Hendrick et al., 2002). The duration and severity of hyperglycemia are strongly correlated with the extent and rate of microvascular complications (Keecia et al., 2005; Bonney et al., 1995; Olsen et al., 2000).
Chronic hyperglycemia, which is considered as principal cause of microvascular complications such as nephropathy and neuropathy (Keecia et al., 2005; Peppa et al., 2003; Selvin et al., 2004; Sasase, 2006; Yen, 2010), can lead to chronic endothelial permeability; an early manifestation of endothelial dysfunction (Bonnardel-Phu et al., 1999; Dang et al., 2005; Algenstaedt et al., 2003) and kidneys, nervous system and ocular system (retina) impairment (Dandona et al., 2004; Lteif et al., 2005; Plante et al., 1995; Kukidome et al., 2006). Improving glycemic condition toward maintaining euglycemia is the most effective strategy for preventing microvascular complications (Yen, 2010) and substantially reduce the incidence of microvascular disease in diabetic patients (Selvin et al., 2004; Shichiri et al., 2000; Kukidome et al., 2006).
Although all diabetic cells are exposed to elevated levels of plasma glucose, hyperglycemic damage is limited to those cell types that are unable to down regulate glucose transport into the cell (e.g., endothelial cells), leading to intra-cellular hyperglycemia (Brownlee, 2001).
In the early stage of diabetes, intracellular hyperglycemia increases blood flow, vascular permeability and intra-capillary pressure (Brownlee, 2001), due to the decreased activity of vasodilators such as nitric oxide (Abi-Chahin et al., 2009), increased activity of vasoconstrictors such as angiotensin II (Schmieder et al., 2009) and endothelin-1 (Papadogeorgos et al., 2009) and permeability factors such as VEGF (Paques et al., 1997; Benjamin, 2001). Consequently, capillaries exhibit increased leakage in some organs. Hyperglycemia may also decreases the production of trophic factors in endothelial and neuronal cells (Russell et al., 1998). Connective Tissue Growth Factor (CTGF) has recently been shown to be over-expressed in kidney, myocardium and aorta in diabetic animals, implicating CTGF role in the pathogenesis of both microvascular and macrovascular diabetic complications (Brownlee, 2001).
Hyperglycemia results in mitochondrial ROS generation (Brownlee, 2005; Nishikawa et al., 2000; Kukidome et al., 2006), which induces oxidative stress through multiple pathways including polyol pathway (Gabbay, 1975), DAG/PKC pathway (Koya and King, 1998; Nishizuka, 1992; Sasase, 2006), AGE formation (Brownlee et al., 1988; Brownlee, 1995) and hexosamine pathway (Nerlich et al., 1998; Schleicher and Weigert, 2000), that subsequently cause endothelial dysfunction and microvascular complications (Zhang and Gutterman., 2007).
DIABETIC NEPHROPATHY (DN)
The DN, which is a major cause of illness and death in diabetic patients, leads to the end-stage renal disease (Czekalski, 2005; Ritz, 1999; Sumiyoshi et al., 2010). About 30% of type 1 and approximately 20 to 30% of type 2 diabetic cases develop diabetic nephropathy (Devi and George, 2008; Rossing et al., 1995; Bakris et al., 2000), which is characterized by persistent albuminuria and proteinuria, progressive reduction of GFR rate and increased morbidity and mortality due to cardiovascular diseases (Devi and George, 2008; Gross et al., 2005; Tarnow et al., 2000; Young et al., 2003; De Zeeuw, 2004). Long term diabetes and poor glycemic control are the most important risk factors for DN development (DCCT Research Group, 1993).
Although in all diabetic patients, GFR is initially normal or mildly elevated with no histological alterations, it progresses to produce thick glomerular basement membrane and expand to mesangial, followed by high glomerular capillary pressure and microalbuminuria. Without intervention, microalbuminuria typically may progresses to macroalbuminuria or proteinuria and overt diabetic nephropathy associated with decline in renal function (Fowler, 2008; Czekalski, 2005; Sumiyoshi et al., 2010). Only 30-45% of microalbuminuric patients develop overt proteinuria after more than 10 years (Caramori et al., 2000).
ETIOLOGY
It has been suggested that advanced glycation end products (AGE) (Makita et al., 1991; Bucala et al., 1991), increase synthesis of cytokines and growth factors (Wolf, 2004; Brownlee, 2001) and diverse glucose metabolism into at least three metabolic pathways; the polyol, the protein kinase C (Park et al., 2000; Brownlee, 2001) and the hexosamine pathways (Brownlee, 2001), which are associated with the pathogenesis of DN. Vascular Endothelial Growth Factor (VEGF), which is an important growth factor involved in DN, is over-expressed at early stages of DN in both diabetic patients and diabetic animal models (Flyvbjerg, 2000; Khamaisi et al., 2003). It has aslo been shown that the blockade of VEGF bioactivity for 6 weeks abolish glomerular hyperfiltration in streptozotocin-induced diabetic rats (De Vriese et al., 2001).
Since the characteristic structural changes of diabetic nephropathy are accompanied by accumulation of AGEs, prolonged infusion of nondiabetic rats with AGEs has led to the development of similar morphological changes and significant proteinuria (Peppa et al., 2003). Likewise, AGE inhibitors such as aminoguanidine were able to prevent diabetic nephropathy in diabetic animal models (Peppa et al., 2003). Studies have also revealed that inflammation plays a crucial role in DN (Janssen et al., 2002; Okada et al., 2003; Shestakova et al., 2002); the migration of immune cells into the kidney is a crucial step in the progression of DN (Galkina and Ley, 2006).
DIABETIC NEUROPATHY
Diabetic neuropathy, which is recognized as the presence of symptoms and/or signs of peripheral nerve dysfunction in diabetic patients (American Diabetes Association, 2007; Boulton et al., 1998a), is a common long-term complication of diabetes affecting up to 50% of patients (Huizinga and Peltier, 2007; Boulton, 2005). The risk factors of developing diabetic neuropathy are the duration and severity of hyperglycaemia (Boulton, 2005), high levels of serum lipids (Boulton, 2005; Rajbhandari and Piya, 2005) and high blood pressure (Boulton, 2005; Forrest et al., 1997). Hyperglycaemia, which increases endoneurial vascular resistance and reduces nerve blood flow, leads to endoneurial hypoxia and subsequently, inhibits axonal transport and nerve infarction (Ali, 2003).
Neuropathy, which is a significant source of disability in elderly diabetic patients (Simmons and Feldman, 2002), affect all peripheral nerves such as sensory (Boulton, 2005; Kannan, 2000), motor and autonomic (Boulton, 2005; Kannan, 2000) nerves. Neuropatheis may be focal or diffusable (Boulton, 2005; Kannan, 2000) and is classified as polyneuropathies and mononeuropathies (Boulton, 2007; Welles, 2003).
Mode of acute sensory neuropathy is relatively rapid (Boulton, 2007), while chronic sensory neuropathy is a length-dependant process (Welles, 2003). Diabetic peripheral neuropathy affects up to 50% of elderly type 2 diabetic patients (Boulton, 2005; Boulton et al., 2004; Cabezas-Cerrato, 1998) and more than 80% of amputations occur after foot ulceration or injury (Boulton, 2005; Katz et al., 2001).
Autonomic neuropathy affects all organs supplied by autonomic nerves (Bhadada et al., 2001) and can cause hypoglycemia unawareness, a condition in which people no longer experience the warning symptoms of low blood glucose levels (Thomas and Tomlinson, 1993; Vinik and Erbas, 2001).
The trigger of diabetic neuropathy is hyperglycemia that appears to result in increased activity of the aldose reductase (polyol) pathway (Yagihashi et al., 2001; Simmons and Feldman, 2002), which leads to the accumulation of sorbitol and fructose (Tornlinson, 1989; Yagihashi et al., 2001), decreases free nerve myoinositol (Winegrade, 1987; Feldman and Vincent, 2004) and imbalances Nicotinamide Adenine Dinucleotide Phosphate (NADP) and its reduced form (Bhadada et al., 2001; Gingliano et al., 1996). Advanced glycation end-product pathway (Rajbhandari and Piya, 2005; Monnier et al., 1986; Vlassara et al., 1983) and hexosamine pathway (Vincent and Feldman, 2004; Feldman and Vincent, 2004) induce inappropriate activation of protein kinase C pathway (Simmons and Feldman, 2002; Rajbhandari and Piya, 2005; Vincent and Feldman, 2004) and formation of reactive oxygen species (Obrosova et al., 2001; Bhadada et al., 2001; Russell et al., 2002; Vincent and Feldman, 2004), alter lipid metabolism (Stevensa et al., 2009) and lead to diabetes-induced defects in growth factors (Stevensa et al., 2009). Available evidence suggests that these various pathogenetic factors act synergistically (Feldman et al., 1997).
DIABETIC RETINOPATHY (DR)
DR, which is defined as microangiopathy of retinal blood vessels, is one of the most common complications of diabetes that causes blindness in working-age individuals (Mohamed et al., 2007; Wild et al., 2004; Balasubramanyam et al., 2002). Damage is caused by both microvascular leakage and occlusion of the inner blood-retinal barrier (Watkins, 2003). Diabetic retinopathy is characterized by early vascular lesions including apoptosis of microvascular cells, formation of pericyte ghosts and the development of acellular capillaries (Mizutani et al., 1996; Hammes, 2005; Garg and Davis, 2009), which eventually lead to hypoxia, followed by impaired vision (Benjamin, 2001; Kramerov et al., 2006).
Retinopathy may begin to develop as early as 7 years before the diagnosis of diabetes in patients with type 2 diabetes (Fong et al., 2004) and its prevalence increases with severity of hyperglycemia (Wong et al., 2008; DCCT Research Group, 1995; Kohner et al., 2001) and duration of diabetes (Klein et al., 1998, 1989). After twenty years of diabetes, almost all and more than 60% of patients with type 1, 2 diabetes will develop some degree of retinopathy, respectively (Fowler, 2008; Mohamed et al., 2007; Watkins, 2003; Balasubramanyam et al., 2002; Klein et al., 1984). Other risk factors for developing of DR include hypertension (Klein et al., 1998; Dharmalingam, 2003; Klein et al., 1995; Snow et al., 2003), family background (DCCT Research Group, 1997), hyperlipidemia (elevated triglycerides and reduced HDL cholesterol) (Kordonouri et al., 1996; Klein et al., 1991; Chew et al., 1996; Van Leiden et al., 2002; Klein et al., 2002), obesity, smoking and puberty (Kordonouri et al., 1996; Holl et al., 1998). DN can be generally classified into nonproliferative (background), proliferative and macular edema (Fowler, 2008; Mohamed et al., 2007; Watkins, 2003).
Background retinopathy: The first visible signs in background (nonproliferative) DR are microaneurysms, which are defined as small vascular dilatations that occur in the retina and small hemorrhages within the compact middle layers of the retina (Watkins, 2003; Garg and Davis, 2009). Hard exudates are caused by lipid deposition that typically occurs at the edge of microvascular leakage and may form a circinate pattern around a leaking microaneurysm (Fowler, 2008; Watkins, 2003).
Progressive capillary blockade is accompanied by ischaemia and hypoxia (Garg and Davis, 2009). Signs of ischaemia include large dark blot haemorrhages, venous beading (Garg and Davis, 2009), intra retinal microvascular abnormalities and white areas on the retina (cotton-wool spots) (Watkins, 2003).
Preproliferative retinopathy: Proliferative diabetic retionopathy occurs with more retinal ischemia and hypoxia, due to microvascular occlusion followed by production of compensatory chemical mediators (most notably VEGF). These mediators induce the growth of fragile new blood vessels, in term of abnormal neovascularization, at the inner surface of the retina, optic disc or iris (rubeosis iridis) (Watkins, 2003; Boulton et al., 1998b). If proliferation continues, these abnormal fragile vessels may bleed into vitreous and finally results in tractional retinal detachment and significant vision loss (Garg and Davis, 2009). The new blood vessels can also expand into the angle of eye anterior chamber and cause neovascular glaucoma (Aiello, 2003; Watkins, 2003; Schmieder et al., 2009).
Diabetic macular edema: Diabetic macular edema is the principal cause of visual deterioration in diabetic patients and caused by breakdown of the inner blood-retinal barrier (Weisbrod and Schwartz, 2009; Rajagopal et al., 2009). It can occur at any stage of DR (Garg and Davis, 2009) and is characterized by the accumulation of hard exudates on the macula (Watkins, 2003).
PATHOGENESIS AND ETIOLOGY
Several biochemical mechanisms including the activation of polyol pathway (Fong et al., 2004; Nishimura et al., 1994), advanced glycosylated end products (AGEs) formation (Degenhardt et al., 1998; Balasubramanyam et al., 2002; Wautier and Guillausseau, 2001), increased hexosamine pathway flux (Nerlich et al., 1998; Schleicher and Weigert, 2000; Nakamura et al., 2001), activation of Protein Kinase C (PKC) (Mohamed et al., 2007; Shiba et al., 1993; Ways and Sheetz, 2000; Galvez, 2009) and oxidative stress (Balasubramanyam et al., 2002; Fong et al., 2004; Nakamura et al., 2001) lead to retinopathy development. These pathways are associated with the production and signaling of angiogenic factors such as Ang 2 (Schmieder et al., 2009) and growth factors including VEGF (Adamis et al., 1994; Boulton et al., 1998a; Aiello et al., 1994; Jardeleza and Miller, 2009; Rajagopal et al., 2009), IGF-I (Fong et al., 2004; Chew et al., 1995), PDGF (Geraldes et al., 2009), bFGF (Balasubramanyam et al., 2002), Ang2 (Schmieder et al., 2009), HGF/SF, PIGF (Balasubramanyam et al., 2002), TGF-β (Pena et al., 1994; Spranger et al., 1999) and PEDF (Dawson et al., 1999; Fong et al., 2004). Moreover, diabetes-induced tumor necrosis factor (TNFα) plays an important role in microvascular cell loss (Behl et al., 2008).
Transcription factor FOXO1, which regulates cell death, inhibits cell cycle progression and modulates differentiation in various cell types (Accili and Arden, 2004; Burgering and Kops, 2002), plays an important role in diabetes-induced apoptosis and retinal micro vascular cell loss via a process mediated by TNF (Behl et al., 2009). Inhibition of FOXO1 by RNA interference technology reduces microvascular cell apoptosis in diabetic retinas in vivo and in vitro (Behl et al., 2009).
Hyperglycemia-induced intramural pericyte death and thickening of the basement membrane (Geraldes et al., 2009) lead to blood-retinal barrier breakdown, retinal capillary nonperfusion and microaneurysm formation (Pardianto, 2005; Watkins, 2003; Weisbrod and Schwartz, 2009).
CHOROID PLEXUS (CP)
The CP is a leaf-like rich vascularized structure protruds into all four ventricles of the brain and produces cerebrospinal fluid (CSF). CP consists of many fenestrated capillaries and separated from the ventricles by choroid epithelial cells and ependymal lining of the ventricles. The external covering of CP acts as a barrier between blood and CSF; blood filters through CP and make CSF.
CEREBROSPINAL FLUID (CSF)
CSF is a major part of CNS extracellular fluid (Brown et al., 2004). It fills all brains ventricles and subarachnoid space surrounding the brain and spinal cord ( Carlson Neil, 2001).
CSF is separated from neuronal tissue by ependyma and pia, which line the ventricles and covers the external surface of the brain, respectively (Brown et al., 2004).
Circulation of CSF begins in the lateral ventricles and it flows into the third and forth ventricles. Then, it flows through a set of openings into the subarachnoid space, which encase the entire central nervous system and finally reabsorbed into the blood supply. The total volume of CSF is approximately 125 mL and its half-life is about 3 h (Carlson Neil, 2001). The CP weigh about 2 g in human, so that the rate of CSF secretion is approximately 0.2 mL min-1 per g of tissue (Brown et al., 2004).
The composition of CSF influences neuronal activity, notably in the central chemoreceptors of the medulla oblongata, that control respiration by responding to changes in CSF pH (Brown et al., 2004).
CSF has a number of important functions; it provides mechanical support for the brain by reducing its net weights (Carlson Neil, 2001; Segal, 1993), it removes products of metabolism or synaptic activity and contribute to the stability of neuronal extracellular environment (Segal, 1993; Weaver et al., 2004) and acts as a route of communication within the CNS by carrying hormones and transmitters between different areas of the brain (Brown et al., 2004).
During fetal development, the brain normal growth depends on the CP-CSF nexus for a steady supply of micronutrients and trophic factors (Weaver et al., 2004).
Since CSF is extracted from blood (Carlson Neil, 2001), the compositions of plasma and CSF is very similar. However, in comparison with plasma, proteins have a greatly reduced concentration in the CSF (Brown et al., 2004) and the concentration of some ions such as K+, HCO3¯ and Ca2+ is carefully regulated in CSF (Husted and Reed, 1976, 1977; Murphy et al., 1986).
Hemodynamics in the plexus acts as a significant factor in matching epithelial transport capacity and intimately connected CSF hydrodynamics. Autoregulation of blood flow normally stabilizes the supply of ions and water to the basolateral (plasma-facing) membrane of the epithelium (Weaver et al., 2004). In response to ischemia and augmented intracranial pressure, AVP and CBFGF-2, which are colocalized in the choroid epithelium, release from blood CSF barrier and help the repair of injured tissue and adjust CSF (Weaver et al., 2004).
CSF secretion: CP secrets Na+, Cl¯ and HCO3¯ and mediate net absorption of K+ from CSF to blood (Wright, 1978). There are net fluxes of other ions such as Ca2+ and organic anions and cations across the CP,that play critical roles for the normal function of the CNS and contribute significantly to the osmotic gradient, which drives CSF secretion (Brown et al., 2004).
The basolateral membrane contains antiporters which are important for choroid plexus pH regulation and Cl¯-HCO3¯ antiporters that move Na+ and Cl¯ from plasma ultrafiltrate into choroid cells in the first step of CSF secretion. HCO3¯ generated from carbonic anhydrase activity inside the cell, along with Na+ and Cl¯ in the cytoplasm, are extruded into the ventricular CSF by primary (Na+-K+-ATPase pump) and secondary (Na+-K+-2Cl¯ cotransport) active transport mechanisms, as well as apical membrane channels (Brown et al., 2004; Weaver et al., 2004). The Na+-K+ ATPase pumps in the apical membrane are responsible for the export of Na+ into CSF (Brown et al., 2004). The Na+-K+-2Cl¯ cotransporter is expressed on both basolateral and apical membranes of the choroid plexus (Plotkin et al., 1997).
Na+-K+ ATP-dependent transport is the main mechanism by which K+ can be transported from CSF into epithelial cells against a large electrochemical gradient. In the mammalian CP, the Kv1 and Kir7.1 channels probably provide the major route for K+ efflux. However, KCC4 may also contribute to K+ efflux at the apical membrane. This recycling of K+ is necessary to limit the transport of K+ across the epithelium, so that CSF does not become denuded of K+.
Furthermore, Cl¯ and HCO3¯ diffuse down electrochemical gradients from cytoplasm to ventricular fluid via specific channels. A cardinal element in this transfer is the movement of Cl¯, which attains a concentration in CSF that is 20% greater than in plasma. To complete the secretory process, water follows the translocated ions osmotically through protein structures in the membrane, i.e., aquaporin pores (AQP1) and cotransporters (Weaver et al., 2004). Biogenic amines, peptides and growth factors can alter ion transport and consequently CSF formation, usually in an inhibitory manner (Nilsson et al., 1992).
Although CSF production is not neurohumorally sensitive to a sudden rise in intracranial pressure, the fluid output by CP seems to be chronically responsive to feedback regulatory mechanisms involving growth factors and neuropeptides (Johanson et al., 1999; Hakvoort and Johanson, 2000; Chodobski and Szmydynger-Chodobska, 2001).
EFFECTS OF DIABETES ON CP
Diabetes is a risk factor for abnormal CSF pressure in hydrocephalus (Casmiro et al., 1989; Krauss et al., 1996; Casmiro et al., 1989) that is caused by excessive retention or production of CSF within the CNS (Casmiro et al., 1989; Tehranipour et al., 2007). Length density of CP capillaries and the volume of lateral ventricles show significant increase in the newborns of hyperglycemic dams (Tehranipour et al., 2008). Furthermore, maternal hyperglycemia may increases the surface of CSF secreting epithelium by abnormal angiogenesis in CP, which leads to imbalance efflux of electrolytes at CSF- blood barrier and increases the ventricular volumes (Tehranipour et al., 2008, 2007). Diabetes can affect the blood-brain-barrier (BBB) permeability and leads to disturbance in ion transport and CSF homeostasis (Tehranipour et al., 2007).
Data obtained from experiments on diabetic animal models indicate the alteration of ion transporters expression (Janicki et al., 1994) including Na+-H+ exchanger (Siczkowski et al., 1995; Dyck and Lopaschuk, 1998; Pierce et al., 1990), Na+-K+-2Cl¯ cotransporter (Michea et al., 2001) and Na+-K+-ATPase (Levy et al., 1986; Tehrani et al., 1990; Kumthekar and Katyare, 1992; Tesfamariam et al., 1993). Similar alterations are reported on perturbations in transport of various ions across the BBB in STZ induced diabetes; Na+and K+ uptake in rat BBB decreased, while Cl¯ and Ca2+ transport did not alter (Jakobsen et al., 1987; Knudsen et al., 1986). It has been shown that in the CP of diabetic rats, the expression of α1-subunit of Na+-K+-ATPase, but not β1- or β2- subunits and Na+-K+-2Cl¯ cotransporter significantly increase. However, the activity of Na+-H+ exchanger reduces (Egleton et al., 2003) and application of Na+-K+-2Cl¯ inhibitors decreases CSF production (Egleton et al., 2003). Unlike plasma K+, CSF K+ level is maintained during hyperkalemia, which alternatively increases Na+-K+-ATPase α1-subunit expression in diabetic rat CP (Egleton et al., 2003; Klarr et al., 1997).
High blood glucose level can phosphorylate Na+-K+-ATPase α1-subunit, at serine and threonine residues, by protein kinase C, which may be linked with the down regulation of activity either by stimulating Na+-K+-ATPase endocytosis or inhibiting its enzyme activity (Chibalin et al., 2001). Conversely, insulin therapy increases the number of Na+-K+-ATPases and elevates its activity (Sweeney et al., 2001) via PKC and tyrosine kinase activity (Chibalin et al., 2001), as well as increasing Na+-H+exchanger activity via PKC-ξ (Egleton et al., 2003).
High blood glucose also inhibits Na+-K+-2Cl¯ activity through the protein kinase C mediated phosphorylation (Layne et al., 2001), while osmotic shock stimulates its activity via PKC-δ mediated phosphoelation (Egleton et al., 2003).
Since the alteration of transporters activity can alter the production of CSF, it is likely that in diabetic animals, the rate of CSF turnover will change and the ability of CP to compensate this alteration in brain extracellular fluid composition may reduce.
The assessment of electrolytes concentration in CSF of infants from diabetic mothers showed that electrolyte concentration in these animals was increased. Subsequently, CSF osmolality increased and finally resulted in too more water reabsorption. These effects could lead to brain disorders such as hydrocephalus (Tehranipour et al., 2007).
PULMONARY COMPLICATIONS OF DIABETES
The reduction of lung function in diabetic patients (Goldman, 2003; McKeeve et al., 2005) may be due to alveolar tissue and capillaries disfunction (Chance et al., 2008) that lead to lung volume restriction (Davis et al., 2004), forced vital capacity (Hsia and Raskin, 2008) and loss of physiological reserves (Hsia, 2002). Hyperglycemia induces alveolar epithelial and capillary endothelial basal lamina thickening (Weynand et al., 1999; Vracko et al., 1979) and fibrosis (Farina et al., 1995), which result in reduced membrane diffusing capacity and pulmonary capillary blood volume (Chance et al., 2008) and restricted alveolar gas transport (Chance et al., 2008; Guvener et al., 2003; Mori et al., 1992) that cause pulmonary microangiopathy (Isotani et al., 1999) and 15-30% reduction of pulmonary capillary blood volume in young nonsmoker type 1 diabetic patients (Ramirez et al., 1991; Niranjan et al., 1997). Impaired alveolar gas transfer in type 1 diabetic patients signifies erosion of microvascular reserves (Chance et al., 2008).
Type 2 diabetes has also been linked to pulmonary dysfunction (Foster et al., 2010), lower spirometric indexes (Davis et al., 2004; Litonjua et al., 2005) and resting lung diffusing capacity for carbon monoxide (Asanuma et al., 1985; Weir et al., 1988), which may be correlate with glycemic control and extrapulmonary microangiopathy (Chance et al., 2008).
CONCLUSION
Diabetic nephropathy, neuropathy and retinopathy are the most common microvascular complications of hyperglycemia and have been well characterized. Since recent reports reveal that hyperglycemia may also affect other microvascular systems, it is worth to pay more attentions on other specialized microvascular systems including CP, alveolar capillaries of lungs and hepatic microvasculature.
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