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Journal of Biological Sciences

Year: 2010 | Volume: 10 | Issue: 5 | Page No.: 411-423
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Research Article

Microvascular Complications of Diabetes

M. Behnam- Rassouli, M.B. Ghayour and N. Ghayour

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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Received: February 26, 2010;   Accepted: April 15, 2010;   Published: July 14, 2010

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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.

REFERENCES

  1. Abi-Chahin, T.C., M.A. Hausen, C.M. Mansano-Marques and V.L.R. de Castro Halfoun, 2009. Microvascular reactivity in type 1 diabetics. Arq Bras Endocrinol. Metab., 53: 741-746.
    PubMed
  2. Accili, D. and K.C. Arden, 2004. FoxOs at the crossroads of cellular metabolism, differentiation and transformation. Cell, 117: 421-426.
    Direct Link
  3. Adamis, A.P., J.W. Miller, M.T. Bernal, D.J. D'Amico and J. Folkman et al., 1994. Elevated vascular permeability factor/vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Ophthalmology, 118: 445-450.
    PubMed
  4. Aiello, L.M., 2003. Perspectives on diabetic retinopathy. Am. J. Ophthalmol., 136: 122-135.
    PubMed
  5. Aiello, L.P., R.L. Avery, P.G. Arrigg, B.A. Keyt and H.D. Jampel et al., 1994. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. New Engl. J. Med., 331: 1480-1487.
    Direct Link
  6. Alberti, K.G.M.M. and P.Z. Zimmet, 1998. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Med., 15: 539-553.
    CrossRefPubMedDirect Link
  7. Algenstaedt, P., C. Schaefer, T. Biermann, A. Hamann and B. Schwarzloh et al., 2003. Microvascular alterations in diabetic mice correlate with level of hyperglycemia. Diabetes, 52: 542-549.
    Direct Link
  8. Ali, R.A., 2003. Management of diabetic neuropathy. Malaysian J. Med. Sci., 10: 27-30.
  9. American Diabetes Association, 2007. Standards of medical care in diabetes-2007. Diabetes Care, 30: S4-S41.
    CrossRefDirect Link
  10. Asanuma, Y., S. Fujiya, H. Ide and Y. Agishi, 1985. Characteristics of pulmonary function in patients with diabetes mellitus. Diabetes Res. Clin. Pract., 1: 95-101.
    PubMed
  11. Bakris, G.L., M. Williams, L. Dworkin, W.J. Elliott, M. Epstein and R. Toto et al., 2000. Preserving renal function in adults with hypertension and diabetes a consensus approach national kidney foundation hypertension and diabetes executive committee working group. Am. J. Kidney Dis., 36: 646-661.
    PubMed
  12. Balasubramanyam, M., M. Rema and C. Premanand, 2002. Biochemical and molecular mechanisms of diabetic retinopathy. Current Sci., 83: 1506-1514.
    Direct Link
  13. Behl, Y., P. Krothapalli, T. Desta, A. Di Piazza, S. Roy and D.T. Graves, 2008. Diabetes enhanced tumor necrosis factor-α production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy. Am. J. Pathol., 172: 1411-1418.
    PubMed
  14. Behl, Y., P. Krothapalli, T. Desta, S. Roy and D.T. Graves, 2009. FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats. Diabetes, 58: 917-925.
    CrossRefDirect Link
  15. Benjamin, L.E., 2001. Glucose, VEGF-A, and diabetic complications. Am. J. Pathol., 158: 1181-1184.
    Direct Link
  16. Bhadada, S.K., R.K. Sahay, V.P. Jyotsna and J.K. Agrawal, 2001. Diabetic neuropathy: Current concepts. Indian Acad.Clin. Med., 2: 305-318.
    Direct Link
  17. Bonnardel-Phu, E., J.L. Wautier, A.M. Schmidt, C. Avila and E. Vicaut, 1999. Acute modulation of albumin microvascular leakage by advanced glycation end products in microcirculation of diabetic rats in vivo. Diabetes, 48: 2052-2058.
    Direct Link
  18. Bonney, M., S.J. Hing, A.T. Fung, M.M. Stephens and J.M. Fairchild et al., 1995. Development and progression of diabetic retinopathy: Adolescents at risk. Diabet Med., 12: 967-973.
    PubMed
  19. Boulton, A.J.M., F.A. Gries and J.A. Jervell, 1998. Guidelines for the diagnosis and outpatient management diabetic peripheral neuropathy. Diabet Med., 15: 508-514.
    CrossRef
  20. Boulton, A.J.M., R.A. Malik, J.S. Arezzo and J.M. Sosenko, 2004. Diabetic somatic neuropathies. Diabetes Care, 27: 1458-1486.
    CrossRefDirect Link
  21. Boulton, A.J.M., 2005. Management of diabetic peripheral neuropathy. Clin. Diabetes, 23: 9-15.
    Direct Link
  22. Boulton, A.J.M., 2007. Medical treatment of symptomatic diabetic neuropathy. Immun. Endocrine Metab. Agents Med. Chem., 7: 79-86.
    CrossRef
  23. Boulton, M., D. Foreman, G. Williams and D. McLeod, 1998. VEGF localisation in diabetic retinopathy. Br. J. Ophthalmol., 82: 561-568.
    Direct Link
  24. Brownlee, M., 1995. Advanced protein glycosylation in diabetes and aging. Annu. Rev. Med., 46: 223-234.
    Direct Link
  25. Brownlee, M., 2001. Biochemistry and molecular cell biology of diabetic complications. Nature, 414: 813-820.
    CrossRefPubMedDirect Link
  26. Brownlee, M., A. Cerami and H. Vlassara, 1988. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N. Engl. J. Med., 318: 1315-1321.
    CrossRefDirect Link
  27. Brownlee, M., 2005. The pathobiology of diabetic complications: A unifying mechanism. Diabetes, 54: 1615-1625.
    CrossRefPubMedDirect Link
  28. Brown, P.D., S.L. Davies, T. Speake and I.D. Millar, 2004. Molecular mechanisms of cerebrospinal fluid production. Neuroscience, 129: 957-970.
    PubMed
  29. Bucala, R., K.J. Tracey and A. Cerami, 1991. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J. Clin. Invest., 87: 432-438.
    CrossRef
  30. Burgering, B.M. and G.J. Kops, 2002. Cell cycle and death control. 2002. Long live Forkheads. Trends. Biochem. Sci., 27: 352-360.
    PubMed
  31. Cabezas-Cerrato, J., 1998. The prevalence of clinical diabetic polyneuropathy in Spain: A study in primary care and hospital clinic groups. Diabetologia, 41: 1263-1269.
    CrossRef
  32. Caramori, M.L., P. Fioretto and M. Mauer, 2000. The need for early predictors of diabetic nephropathy risk is albumin excretion rate sufficient. Diabetes, 49: 1399-1408.
    PubMed
  33. Carlson Neil, R., 2001. Physiological Psychology. 5th Edn., Allyn and Bacon Press, Boston, MA., pp: 69.
  34. Casmiro, M.D., R. Alessandro, F.M. Cacciatore, R. Daidone, F. Calbucci and E. Lugaresi, 1989. Risk factors for the syndrome of ventricular enlargement with gait apraxia. J. Neurol. Neurosurg. Psych., 52: 847-852.
    PubMed
  35. Chance, W.W., C. Rhee and C. Yilmaz, 2008. Diminished alveolar microvascular reserves in type 2 diabetes reflect systemic microangiopathy. Diabetes Care, 31: 1596-1601.
    CrossRef
  36. Chew, E.Y., M.L. Klein, F.L. Ferris, N.A. Remaley and R.P. Murphy et al., 1996. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy: The Early Treatment Diabetic Retinopathy Study (ETDRS) report No. 22. Arch. Ophthalmol., 114: 1079-1084.
    Direct Link
  37. Chew, E.Y., J.L. Mills, B.E. Metzger, N.A. Remaley and L. Jovanovic-Peterson et al., 1995. Metablolic control and progression of retinopathy: The diabetes in early pregnancy study. National institute of child health and human development diabetes in early pregnancy study. Diabetes Care, 18: 631-637.
    CrossRefDirect Link
  38. Chibalin, A.V., M.V. Kovalenko, J.W. Ryder, E. Feraille, H. Wallberg-Henriksson and J.R. Zierath, 2001. Insulin- and glucose-induced phosphorylation of the Na+, K+-adenosine triphosphatase α-subunits in rat skeletal muscle. Endocrinology, 142: 3474-3482.
    PubMed
  39. Chodobski, A. and J. Szmydynger-Chodobska, 2001. Choroid plexus: Target for polypeptides and site of their synthesis. Microsc. Res. Tech., 52: 65-82.
    PubMed
  40. Czekalski, S., 2005. Diabetic nephropathy and cardiovascular diseases. Roczniki Akademii Medycznej w Białymstoku, 50: 122-125.
    PubMed
  41. Dandona, P., A. Aljada, A. Chaudhuri and P. Mohanty, 2004. Endothelial dysfunction, inflammation and diabetes. Rev. Endocrine Metab. Disorders, 5: 189-197.
    CrossRefPubMedDirect Link
  42. Dang, L., J.P. Seale and X. Qu, 2005. High glucose-induced human umbilical vein endothelial cell hyperpermeability is dependent on protein kinase C activation and independent of the Ca2+-nitric oxide signalling pathway. Clin. Exp. Pharmacol. Physiol., 32: 771-776.
    PubMed
  43. Davis, W.A., M. Knuiman, P. Kendall, V. Grange and T.M. Davis, 2004. Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: The fremantle diabetes study. Diabetes Care, 27: 752-757.
    CrossRef
  44. Dawson, D.W., O.V. Volpert, P. Gillis, S.E. Crawford, H. Xu, W. Benedict and N.P. Bouck, 1999. Pigment epithelium-derived growth factor: A potent inhibitor of angiogenesis. Science, 285: 245-248.
    PubMed
  45. DCCT Research Group, 1997. Clustering of complications in families with diabetes in the DCCT. Diabetes, 46: 1829-1839.
    CrossRef
  46. DCCT Research Group, 1995. Progression of retinopathy with intensive versus conventional treatment in the diabetes control and complications trial. Ophthalmology, 102: 647-661.
    PubMed
  47. Degenhardt, T.P., S.R. Thorpe and J.W. Baynes, 1998. Chemical modification of proteins by methylglyoxal. Cell Mol. Biol., 44: 1139-1145.
    PubMed
  48. Devi, P. and J. George, 2008. Drug information needs of physicians treating diabetic nephropathy in a tertiary care hospital. Kathmandu Uni. Med. J., 6: 23-27.
    PubMed
  49. De Vriese, A.S., R.G. Tilton, M. Elger, C.C. Stephan, W. Kriz and N.H. Lameire, 2001. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J. Am. Soc. Nephrol., 12: 993-1000.
    PubMedDirect Link
  50. De Zeeuw, D., 2004. Albuminuria, not only a cardiovascular/renal risk marker, but also a target for treatment?. Kidney Int., 66: S2-S6.
    CrossRefDirect Link
  51. Dharmalingam, M., 2003. Diabetic retinopathy-risk factors and strategies in prevention. INT. J. Diab. Dev. Countries, 11: 10-13.
    Direct Link
  52. Dyck, J.R. and G.D. Lopaschuk, 1998. Glucose metabolism, H_production and Na+/H+-exchanger mRNA levels in ischemic hearts from diabetic rats. Mol. Cell Biochem., 180: 85-93.
    PubMed
  53. Egleton, R.D., C. Campos, J. Huber, R. Brown and T. Davis, 2003. Differential effects of diabetes on rat choroids plexus ion transporter expression. Diabetes, 52: 1496-1501.
    PubMed
  54. Farina, J., V. Furio, M.J. Fernandez-Acenero and M.A. Muzas, 1995. Nodular fibrosis of the lung in diabetes mellitus. Virchows Arch., 427: 61-63.
    CrossRef
  55. Feldman, E.L. and A. Vincent, 2004. The prevalence, impact and multifactorial pathogenesis of diabetic peripheral neuropathy. Adv. Stud. Med., 4: 642-649.
  56. Feldman, E.L., M.J. Stevens and D.A. Greene, 1997. Pathogenesis of diabetic neuropathy. Clin. Neurosci., 4: 365-370.
    PubMed
  57. Forrest, K.Y., R.E. Maser, G. Pambianco, D.J. Becker and T.J. Orchard, 1997. Hypertension as a risk factor for diabetic neuropathy: A prospective study. Diabetes, 46: 665-670.
    PubMed
  58. Foster, D.J., P. Ravikumar, D.J. Bellotto, R.H. Unger and C.C.V. Hsia, 2010. Fatty diabetic lung: Altered alveolar structure and surfactant protein expression. Am. J. Physiol. Lung Cell Mol. Physiol., 298: 392-403.
    CrossRef
  59. Flyvbjerg, A., 2000. Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. Diabetologia, 43: 1205-1223.
    PubMed
  60. Fong, D.S., L.P. Aiello, F.L. Ferris and R. Klein, 2004. Diabetic retinopathy. Diabetes Care, 27: 2540-2553.
    Direct Link
  61. Fowler, M.J., 2008. Microvascular and macrovascular complications of diabetes. Clin. Diabetes, 26: 77-82.
    CrossRefDirect Link
  62. Gabbay, K.H., 1975. Hyperglycemia, polyol metabolism, and complications of diabetes mellitus. Annu. Rev. Med., 26: 521-536.
    PubMed
  63. Galkina, E. and K. Ley, 2006. Leukocyte recruitment and vascular injury in diabetic nephropathy. J. Am. Soc. Nephrol., 17: 368-377.
    CrossRefDirect Link
  64. Galvez, M.I.L., 2009. Rubosixtaurin and other pkc inhibitors in diabetic retinopathy and macular edema. Rev. Curr. Diabetes Rev., 5: 14-17.
    PubMed
  65. Garg, S. and R.M. Davis, 2009. Diabetic retinopathy screening update. Clin. Diabetes, 27: 140-145.
    CrossRefDirect Link
  66. Geraldes, P., J. Hiraoka-Yamamoto and M. Matsumoto, 2009. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med., 15: 1298-1306.
    CrossRefDirect Link
  67. Gerrits, E.G., H.L. Lutgers, N. Kleefstra, R. Graaff and K.H. Groenier et al., 2008. Skin Autofluorescence, A tool to identify type 2 diabetic patients at risk for developing microvascular complications. Diabetes Care, 31: 517-521.
    CrossRefDirect Link
  68. Gingliano, D., A. Ceriello and G. Pawlisso, 1996. Oxidalive stress and diabetic vascular complications. Diabetes Care, 19: 257-267.
    PubMed
  69. Goldman, M.D., 2003. Lung dysfunction in diabetes. Diabetes Care, 26: 1915-1918.
    CrossRefDirect Link
  70. Gross, J.L., M.J. de Azevedo, S.P. Silveiro, L.H. Canani, M.L. Caramori and T. Zelmanovitz, 2005. Diabetic nephropathy: Diagnosis, prevention and treatment. Diabetes Care, 28: 164-176.
    CrossRefPubMedDirect Link
  71. Guvener, N., N.B. Tutuncu, S. Akcay, F. Eyuboglu and A. Gokcel, 2003. Alveolar gas exchange in patients with type 2 diabetes mellitus. Endocr. J., 50: 663-667.
    Direct Link
  72. Hammes, H.P., 2005. Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab. Res., 37: 39-43.
    PubMed
  73. Hakvoort, A. and C.E. Johanson, 2000. Growth factor modulation of CSF formation by isolated choroid plexus: FGF-2 vs. TGF-B1. Eur. J. Pediatr. Surg., 10: 44-46.
    PubMed
  74. Hendrick, A.L., M.D. Jacqueline, C.M. Annette, G. Nejpels and J.H. Robert, 2002. Blood pressure, lipids and obesity are associated with retinopathy. Diabetes Care, 25: 1320-1325.
    CrossRef
  75. Hsia, C.C., 2002. Recruitment of lung diffusing capacity: Update of concept and application. Chest, 122: 1774-1783.
  76. Hsia, C.C.W. and P. Raskin, 2008. Lung involvement in diabetes. Does it matter? Diabetes Care, 31: 828-829.
    PubMed
  77. Holl, R.W., G.E. Lange and M. Grahart, 1998. Diabetic retinopathy in pediatric patients with type 1 diabetes: Effect of diabetes duration, prepubertal and pubertal onset of diabetes and metabolic control. J. Pediatr., 132: 790-794.
    Direct Link
  78. Huizinga, M.M. and A. Peltier, 2007. Painful diabetic neuropathy: A management-centered review. Clin. Diabetes, 25: 6-15.
    CrossRefDirect Link
  79. Husted, R.F. and D.J. Reed, 1977. Regulation of cerebrospinal fluid bicarbonate by the cat choroid plexus. J. Physiol., 267: 411-428.
    Direct Link
  80. Husted, R.F. and D.J. Reed, 1976. Regulation of cerebrospinal fluid potassium by the cat choroid plexus. J. Physiol., 259: 213-221.
    Direct Link
  81. Isotani, H., Y. Nakamura, K. Kameoka, K. Tanaka, K. Furukakawa, H. Kitaoka and N. Ohsawa, 1999. Pulmonary diffusion capacity, serum angiotensinconverting enzyme activity and angiotensin-converting enzyme gene in Japanese non insulin-dependent diabetes mellitus patients. Diabetes Res. Clin. Pract., 43: 173-177.
    Direct Link
  82. Jakobsen, J., G.M. Knudsen and M. Juhler, 1987. Cation permeability of the blood-brain barrier in streptozotocin-diabetic rats. Diabetologia, 30: 409-413.
    CrossRef
  83. Janicki, P.K., J.L. Horn, G. Singh, W.T. Franks and J.J. Franks, 1994. Diminished brain synaptic plasma membrane Ca2+-ATPase activity in rats with streptozocin-induced diabetes: Association with reduced anesthetic requirements. Life Sci., 55: 39-64.
    PubMed
  84. Janssen, U., E. Sowa, P. Marchand, J. Floege, A.O. Phillips and H.H. Radekem, 2002. Differential expression of MCP-1 and its receptor CCR2 in glucose primed human mesangial cells. Nephron, 92: 797-806.
    CrossRefDirect Link
  85. Jardeleza, M.S.R. and J.W. Miller, 2009. Review of Anti-VEGF therapy in proliferative diabetic retinopathy. Seminars Ophthalmol., 24: 87-92.
    CrossRef
  86. Johanson, C.E., J. Szmydynger-Chodobska, A. Chodobski, A. Baird, P. McMillan and E.G. Stopa, 1999. Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus. Am. J. Physiol., 277: R263-R271.
    Direct Link
  87. Kannan, V., 2000. Molecular mechanism of diabetic neuropathy. Int. J. Diab. Dev. Countries, 20: 101-103.
  88. Katz, J.S., D.S. Saperstein and G. Wolfe, 2001. Cervicobrachial involvement in diabetic radiculoplexopathy. Muscle Nerve, 24: 794-798.
    PubMed
  89. Keecia, D.K., J.D. Jones and W. Jessica, 2005. Microvascular and macrovascular complications of diabetes mellitus. Am. J. Pharmaceutical Educ., 69: 1-10.
    Direct Link
  90. Khamaisi, M., B.F. Schrijvers, A.S. De Vriese, I. Raz and A. Flyvbjerg, 2003. The emerging role of VEGF in diabetic kidney disease. Nephrol Dial Transplant, 18: 1427-1430.
    Direct Link
  91. Klarr, S.A., L.J. Ulanski, W. Stummer, J. Xiang, A.L. Betz and R.F. Keep, 1997. The effects of hypo- and hyperkalemia on choroid plexus potassium transport. Brain Res., 758: 39-44.
    CrossRef
  92. Klein, B.E.K., S.E. Moss, R. Klein and T.S. Surawicz, 1991. The wisconsin epidemiologic study of diabetic retinopathy. XLL: Relation-ship of serum cholesterol to retinopathy and hard exudates. Ophthalmology, 98: 1261-1265.
  93. Klein, R., B.E. Klein, S.E. Moss and K.J. Cruickshanks, 1995. wisconsin epidemiologic study of diabetic retinopathy. XV. The long-term incidence of macular edema Ophthalmology. Ophthalmology, 102: 7-16.
    Direct Link
  94. Klein, R., B.E. Klein, S.E. Moss and K.J. Cruickshanks, 1998. The wisconsin epidemiologic study of diabetic retinopathy, XVII: The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type1 diabetes. Ophthalmology, 105: 1801-1815.
    Direct Link
  95. Klein, R., B.E. Klein, S.E. Moss, M. Davis and D. DeMets, 1984. The wisconsin epidemiological study of diabetic retinopathy II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch. Ophthalmol., 102: 520-526.
    PubMed
  96. Klein, R., B.E. Klein, S.E. Moss, M.D. Davis and D.L. DeMets, 1989. The wisconsin epidemiologic study of diabetic retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch. Ophthalmol., 107: 237-243.
    Direct Link
  97. Klein, R., A.R. Sharrett, B.E. Klein, S.E. Moss and A.R. Folsom et al., 2002. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: The atherosclerosis risk in communities study. Ophthalmology, 109: 1225-1234.
    PubMed
  98. Knudsen, G.M., J. Jakobsen, M. Juhler and O.B. Paulson, 1986. Decreased blood-brain barrier permeability to sodium in early experimental diabetes. Diabetes, 35: 1371-1373.
    PubMed
  99. Kohner, E.M., I.M. Stratton, S.J. Aldington, R.R. Holman, D.R. Matthews and UK Prospective Diabetes Study (UKPDS) Group, 2001. Relationship between the severity of retinopathy and progression to photocoagulation in patients with type 2 diabetes mellitus in the UKPDS (UKPDS 52). Diabetes Med., 18: 178-184.
    PubMed
  100. Kordonouri, O., T.H. Danne and W. Hopfenmuller, 1996. Lipid profiles and blood pressure: Are they risk factors for the development of early background retinopathy and incipient nephropathy in children with insulin dependent diabetes mellitus?. Acta Paediatr., 85: 43-48.
    PubMed
  101. Koya, D. and G.L. King, 1998. Protein kinase C activation and the development of diabetic complications. Diabetes, 47: 859-866.
    CrossRefDirect Link
  102. Kramerov, A.A., M. Saghizadeh, H. Pan, A. Kabosova and M. Montenarh et al., 2006. Expression of protein kinase CK2 in astroglial cells of normal and neovascularized retina. Am. J. Pathol., 168: 1722-1736.
    Direct Link
  103. Krauss, J.K., J.P. Regel, W. Vach, D.W. Droste, J.J. Borremans and T. Mergner, 1996. Vascular risk factors and arteriosclerotic disease in idiopathic normalpressure hydrocephalus of the elderly. Stroke, 27: 24-29.
    Direct Link
  104. Kumthekar, M.M. and S.S. Katyare, 1992. Altered kinetic attributes of Na++K+-ATPase activity in kidney, brain and erythrocyte membranes in alloxan-diabetic rats. Indian J. Exp. Biol., 30: 26-32.
    Direct Link
  105. Kukidome, D., T. Nishikawa, K. Sonoda, K. Imoto and K. Fujisawa et al., 2006. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes, 55: 120-127.
    CrossRefDirect Link
  106. Layne, J., S.Yip and R.B. Crook, 2001. Down-regulation of Na-K-Cl cotransport by protein kinase C is mediated by protein phosphatase 1 in pigmented ciliary epithelial cells. Exp. Eye Res., 72: 371-379.
    PubMed
  107. Levy, J., L.V. Avioli, M.L. Roberts and J.R. Gavin, 1986. Na+-K+-ATPase activity in kidney basolateral membranes of non insulin dependent diabetic rats. Biochem. Biophys. Res. Commun., 139: 1313-1319.
    CrossRef
  108. Litonjua, A.A., R. Lazarus, D. Sparrow, D. Demolles and S.T. Weiss, 2005. Lung function in type 2 diabetes: The normative aging study. Respir. Med., 99: 1583-1590.
    Direct Link
  109. Lteif, A.A., K. Han and K.J. Mather, 2005. Obesity, insulin resistance and the metabolic syndrome: Determinants of endothelial dysfunction in whites and blacks. Circulation, 112: 32-38.
    PubMed
  110. Makita, Z., S. Radoff, E.J. Rayfield, Z. Yang and E. Skolnik et al., 1991. Advanced glycosylation end products in patients with diabetic nephropathy. N Engl. J. Med., 325: 836-842.
    Direct Link
  111. McKeeve, T.M., P.J. Weston, R. Hubbard and A. Fogarty, 2005. Lung function and glucose metabolism: An analysis of data from the third national health and nutrition examination survey. Am. J. Epidemiol., 161: 546-556.
    CrossRefDirect Link
  112. Michea, L., V. Irribarra, I.A. Goecke and E.T. Marusic, 2001. Reduced Na-K: Pump but increased Na-K-2Cl cotransporter in aorta of streptozotocin-induced diabetic rat. Am. J. Physiol., 280: H851-H858.
    Direct Link
  113. Mizutani, M., T.S. Kern and M. Lorenzi, 1996. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J. Clin. Invest., 97: 2883-2890.
    Direct Link
  114. Mohamed, Q., M.C. Gillies and T.Y. Wong, 2007. Management of diabetic retinopathy: A systematic review. JAMA., 298: 902-916.
    Direct Link
  115. Monnier, V.M., V. Vishwanath and K.E. Frank, 1986. Relation between complication of type 1 diabetes mellitus and collagen linked fluroscence. N Engl. J. Med., 314: 403-408.
    Direct Link
  116. Mori, H., M. Okubo, M. Okamura, K. Yamane and S. Kado et al., 1992. Abnormalities of pulmonary function in patients with non-insulin-dependent diabetes mellitus. Intern. Med., 31: 189-193.
  117. Murphy, V.A., Q.R. Smith and S.I. Rapoport, 1986. Homeostasis of brain and cerebrospinal fluid calcium concentrations during chronic hypo- and hypercalcemia. J. Neurochem., 47: 1735-1741.
    PubMed
  118. Nakamura, M., A.J. Barber, D.A. Antonetti, K.F. LaNoue, K.A. Robinson, M.G. Buse and T.W. Gardner, 2001. Excessive hexosamines block the neuroprotective effect of insulin and induce apoptosis in retinal neurons. J. Biol. Chem., 276: 43748-43755.
    CrossRef
  119. Nerlich, A.G., U. Sauer, V. Kolm-Litty, E. Wagner, M. Koch and E.D. Schleicher, 1998. Expression of glutamine: Fructose-6-phosphate amidotransferase in human tissues: Evidence for high variability and distinct regulation in diabetes. Diabetes, 47: 170-178.
    CrossRefDirect Link
  120. Nilsson, C., M. Lindvall-Axelsson and C. Owman, 1992. Neuroendocrine regulatory mechanisms in the choroid plexus-cerebrospinal fluid system. Brain Res. Rev., 17: 109-138.
  121. Niranjan, V., D.G. McBrayer, L.C. Ramirez, P. Raskin and C.C.W. Hsia, 1997. Glycemic control and cardiopulmonary function in patients with insulin-dependent diabetes mellitus. Am. J. Med., 103: 504-513.
    PubMed
  122. Nishikawa, T., D. Edelstein, X.L. Du, S. Yamagishi and T. Matsumura et al., 2000. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature, 404: 787-790.
    PubMed
  123. Nishimura, C., T. Saito, T. Ito, Y. Omori and T. Tanimoto, 1994. High levels of erythrocyte aldose reductase and diabetic retinopathy in NIDDM patients. Diabetologia, 37: 328-330.
    CrossRef
  124. Nishizuka, Y., 1992. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science, 258: 607-614.
    CrossRef
  125. Obrosova, I.G., L. Fathallah and M.J. Stevens, 2001. Taurine counteracts oxidative stress and nerve growth factor deficit in early experimental diabetic neuropathy. Exp. Neurol., 172: 211-219.
    PubMed
  126. Olsen, B.S., A.K. Sjolie, P. Hougaard, J. Johannesen and K. Borch-Johnsen et al., 2000. A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy and neuropathy. Danish study group of diabetes in childhood. J. Diabetes Complications, 14: 295-300.
    PubMed
  127. Okada, S., K. Shikata, M. Matsuda, D. Ogawa and H. Usui et al., 2003. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes, 52: 2586-2593.
    CrossRefDirect Link
  128. Papadogeorgos, N.O., M. Bengtsson and M. Kalani, 2009. Selective endothelin A-receptor blockade attenuates coronary microvascular dysfunction after coronary stenting in patients with type 2 diabetes. Vasc Health Risk Manage., 5: 893-899.
    Direct Link
  129. Paques, M., P. Massin and A. Gaudric, 1997. Growth factors and diabetic retinopathy. Diabetes Metab., 23: 125-130.
    PubMed
  130. Pardianto, G., 2005. Understanding diabetic retinopathy. Mimbar Ilmiah Oftalmologi Indonesia, 2: 65-66.
  131. Park, C.W., J.H. Kim, J.H. Lee, Y.S. Kim and H.J. Ahn et al., 2000. High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NFkappa B-dependent. Diabetologia, 43: 1544-1553.
    PubMed
  132. Pena, R.A., J.A. Jerdan and G.M. Glaser, 1994. Effects of TGF-beta and TGF-beta neutralizing antibodies on fibroblast-induced collagen gel contraction: Implications for proliferative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci., 35: 2804-2808.
    Direct Link
  133. Peppa, M., J. Uribarri and H. Vlassara, 2003. Glucose, advanced glycation end products and diabetes complications: What is new and what works. Clin. Diabetes, 21: 186-187.
    CrossRef
  134. Pierce, G.N., B. Ramjiawan, N.S. Dhalla and R. Ferrari, 1990. Na+-H+ exchange in cardiac sarcolemmal vesicles isolated from diabetic rats. Am. J. Physiol., 258: 255-261.
    Direct Link
  135. Plante, G.E., M. Chakir, S. Lehoux and M. Lortie, 1995. Disorders of body fluid balance: A new look into the mechanisms of disease. Can. J. Cardiol., 11: 788-802.
    PubMed
  136. Plotkin, M.D., M.R. Kaplan, L.N. Peterson, S.R. Gullans, S.C. Hebert and E. Delpire, 1997. Expression of the Na+-K+-2Cl- cotransporter BSC2 in the nervous system. Am. J. Physiol., 272: C173-C183.
    Direct Link
  137. Rajagopal, J., A.G. Kamath G.G. Kamath and N. Solanki, 2009. Foveal neovascularisation in diabetic retinopathy: Case report and review of literature. Int. Ophtalmol.
    CrossRefDirect Link
  138. Rajbhandari, S.M. and M.K. Piya, 2005. A brief review on the pathogenesis of human diabetic neuropathy: Observation and postulations. Int. J. Diabet. Metabolism., 13: 135-140.
  139. Ramirez, L.C., A. Dal Nogare, C.C.W. Hsia, C. Arauz, S. Strowig, L. Schnurrbreen and P. Raskin, 1991. Relationship between diabetes control and pulmonary function in insulin dependent diabetes mellitus. Am. J. Med., 91: 371-376.
    PubMed
  140. Ritz, E., 1999. End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. Am. J. Kidney Disease, 34: 795-808.
    CrossRefPubMedDirect Link
  141. Rossing, P., K. Rossing, P. Jacobsen and H.H. Parving, 1995. Unchanged incidence of diabetic nephropathy in IDDM patients. Diabetes, 44: 739-743.
    CrossRef
  142. Russell, J.W., D. Golovoy, A.M. Vincent, P.I.A. Mahendru, J.A. Olzmann, A. Mentzer and E.L. Feldman, 2002. High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J., 16: 1738-1748.
    CrossRefDirect Link
  143. Russell, J.W., A.J. Windebank, A. Schenone and E.L. Feldman, 1998. Insulin-like growth factor-1 prevents apoptosis in neurons after growth factor withdrawal. J. Neurobiol., 36: 455-467.
  144. Sasase, T., 2006. PKC: A target for treating diabetic complications. Drugs Fut, 31: 503-503.
    CrossRefDirect Link
  145. Schleicher, E.D. and C. Weigert, 2000. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int., 88: 12-18.
    CrossRefDirect Link
  146. Schmieder, R.E., S. Martin, G.E. Lang, P. Bramlage and M. Bohm, 2009. Angiotensin blockade to reduce microvascular damage in diabetes mellitus. Dtsch Arztebl Int., 106: 556-562.
    CrossRefDirect Link
  147. Schwarzenberg, S.J., W. Thomas, T.W. Olsen, T. Grover, D. Walk, C. Milla and A. Moran, 2007. Microvascular complications in cystic fibrosis-related diabetes. Diabetes Care, 30: 1056-1061.
    CrossRefDirect Link
  148. Segal, M.B., 1993. Extracellular and cerebrospinal fluid. J. Inherit. Metabol. Dis., 16: 617-638.
    PubMed
  149. Selvin, E., S. Marinopoulos, G. Berkenblit, T. Rami and F.L. Brancati et al., 2004. Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann. Intern. Med., 141: 421-431.
    PubMed
  150. Shestakova, M.V., T.V. Kochemasova, V.A. Gorelysheva and T.V. Osipova et al., 2002. [The role of adhesion molecules (ICAM-1 and E-selectin) in development of diabetic microangiopathies]. Terapevticheskii Arkhiv, 74: 24-27.
    PubMed
  151. Shichiri, M., H. Kishikawa, Y. Ohkubo and N. Wake, 2000. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care, 23: 21-29.
    Direct Link
  152. Shiba, T., T. Inoguchi, J.R. Sportsman, W.F. Heath, S. Bursell and G.L. King, 1993. Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am. J. Physiol., 265: 783-793.
    Direct Link
  153. Siczkowski, M., J.E. Davies, F.P. Sweeney, A. Kofoed-Enevoldsen and L.L. Ng, 1995. Na+/H+ exchanger isoform-1 abundance in skin fibroblasts of type I diabetic patients with nephropathy. Metabolism, 44: 791-795.
    PubMed
  154. Simmons, Z. and E.L. Feldman, 2002. Update on diabetic neuropathy. Curr. Opin. Neurol., 15: 595-603.
    PubMed
  155. Snow, V., K.B. Weiss and C. Mottur-Pilson, 2003. Clinical efficacy assessment subcommittee of the american college of physicians: The evidence base for tight blood pressure control in the management of type 2 diabetes mellitus. Ann. Int. Med., 138: 587-592.
    Direct Link
  156. Spranger, J., R. Meyer-Schwickerath, M. Klein, H. Schatz and A. Pfeiffer, 1999. Deficient activation and different expression of transforming growth factor-B isoforms in active proliferative diabetic retinopathy and neovascular eye disease. Exp. Clin. Endocrinol., 107: 21-28.
    PubMed
  157. Stevensa, M.J., E.L. Feldmanb and D.A. Greenea, 2009. The aetiology of diabetic neuropathy: The combined roles of metabolic and vascular defects. J. Diabetes UK., 12: 566-579.
    CrossRef
  158. Sumiyoshi, K., C. Kawata, K. Shikata and H. Makino, 2010. Influencing factors for dietary behaviors of patients with diabetic nephropathy. Acta Med. Okayama, 64: 39-47.
    PubMed
  159. Sweeney, G., W. Niu, V.A. Canfield, R. Levenson and A. Klip, 2001. Insulin increases plasma membrane content and reduces phosphorylation of Na+-K+ pump α1-subunit in HEK-293 cells. Am. J. Physiol., 281: 1797-1803.
    Direct Link
  160. Tarnow, L., C. Gluud and H.H. Parving, 1998. Diabetic nephropathy and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene. Nephrol Dial Transplant, 13: 1125-1130.
    Direct Link
  161. Tarnow, L., P. Rossing, F.S. Nielsen, J.A. Fagerudd, O. Poirier and H.H. Parving, 2000. Cardiovascular morbidity and early mortality cluster in parents of type 1 diabetic patients with diabetic nephropathy. Diabetes Care, 23: 30-33.
    CrossRef
  162. Tehranipour, M., M. Behnam Rassouli and A. Rahimi, 2008. Maternal diabetes proliferate the choroid plexus and enlarge the lateral ventricle in brain of newborn rats. J. Biol. Sci., 15: 147-147.
    Direct Link
  163. Tehranipour, M., R. Haeri, M.B. Rassouli, K. Parivar and A. Rahimi, 2007. Determanation of the cerebrospinal fluid electrolytes alteration in the developing rats born from diabetic mothers. J. Biol. Sci., 7: 969-972.
  164. Tehrani, S.T., J.J. Yamamoto and M.H. Garner, 1990. Na(+)-K(+)-ATPase and changes in ATP hydrolysis, monovalent cation affinity and K+ occlusion in diabetic and galactosemic rats. Diabetes, 39: 1472-1478.
    CrossRef
  165. Tesfamariam, B., S. Gupta, P.J. Oates, N.B. Ruderman and R.A. Cohen, 1993. Reduced Na(_)-K_ pump activity in diabetic rabbit carotid artery: Reversal by aldose reductase inhibition. Am. J. Physiol., 265: 1189-1194.
    PubMed
  166. DCCT Research Group, 1993. The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: The diabetes control and complications trial. New Engl. J. Med., 329: 977-986.
  167. Thomas, P.K. and D.R. Tomlinson, 1993. Diabetic and Hypoglycemic Neuropathy. In: Peripheral Neuropathy, Dyck, P.J., P.K. Thomas, J.W. Griffin, P.A. Low and J.F. Poduslo (Eds.). 3rd Edn., W.B. Saunders, Philadelphia, pp: 1219-1250.
  168. Tornlinson, D.R., 1989. Polyols and myointositol in diabetic neuropathy of mice and men. Mayo Clin. Proc., 64: 1030-1030.
  169. UK Prospective Diabetes Study Group, 1998. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br. Med. J., 317: 703-713.
    PubMed
  170. Van Leiden, H.A., J.M. Dekker, A.C. Moll, G. Nijpels and R.J. Heine et al., 2002. Blood pressure, lipids and obesity are associated with retinopathy: The hoorn study. Diabetes Care, 25: 1320-1325.
    PubMed
  171. Vincent, A.M. and E.L. Feldman, 2004. New insights into the mechanisms of diabetic neuropathy. Rev. Endocrine Metabolic Disorders, 5: 227-236.
    CrossRefPubMed
  172. Vincent, A.M., J.A. Olzmann, M. Brownlee, W.I. Sivitz and J.W. Russell, 2004. Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Diabetes, 53: 726-734.
    CrossRefDirect Link
  173. Vinik, A.I. and T. Erbas, 2001. Recognizing and treating diabetic autonomic neuropathy. Cleveland Clinic J. Med., 68: 928-944.
    PubMedDirect Link
  174. Vlassara, H., M. Brownlee and A. Cerami, 1983. Excessive non enzymatic glycosylation of peripheral and central nervous system myelin components in diabetic rats. Diabetes, 32: 670-674.
    CrossRefDirect Link
  175. Vracko, R., D. Thorning and T.W. Huang, 1979. Basal lamina of alveolar epithelial and capillaries. Quantitative changes with aging and diabetes mellitus. Am. Rev. Respir. Dis., 120: 973-983.
    PubMed
  176. Watkins, P.J., 2003. ABC of diabetes Retinopathy. BMJ., 326: 924-926.
    CrossRefDirect Link
  177. Wautier, J.L. and P.J. Guillausseau, 2001. Advanced glycation end products, their receptors and diabetic angiopathy. Diabete Metab., 27: 535-542.
    PubMed
  178. Ways, D.K. and M.J. Sheetz, 2000. The role of protein kinase C in the development of the complications of diabetes. Vitam Horm, 60: 149-193.
    PubMed
  179. Weaver, C.E., P.N. Mc-Millan, J.A. Duncan, E.G. Stopa and C.E. Johanson, 2004. Hydrocephalus disorders: Their biophysical and neuroendocrine impact on the choroid plexus epithelium. Adv. Mol. Cell Biol., 31: 269-293.
  180. Weir, D.C., P.E. Jennings, M.S. Hendy, A.H. Barnett and P.S. Burge, 1998. Transfer factor for carbon monoxide in patients with diabetes with and without microangiopathy. Thorax, 43: 725-726.
    CrossRefDirect Link
  181. Weisbrod, D. and C. Schwartz, 2009. A review of diabetic retinopathy. Ophthalmol. Rounds, Vol. 7.
    Direct Link
  182. Welles, R.V., 2003. Diabetic polyneuropathy: A review of the need for early diagnosis and treatment. Diabetes Symposium, 72: 13-17.
  183. Weynand, B., A. Jonckheere and A. Frans, 1999. Diabetes mellitus induces a thickening of the pulmonary basal lamina. Respiration, 66: 14-19.
    PubMed
  184. Wild, S., G. Roglic, A. Green, R. Sicree and H. King, 2004. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care, 27: 1047-1053.
    CrossRefPubMedDirect Link
  185. Winegrade, A.l., 1987. Does a common mechanism induce the diverse complications of diabetes?. Diabetes, 36: 396-406.
    PubMed
  186. Wolf, G., 2004. New insights into the pathophysiology of diabetic nephropathy: From haemodynamics to molecular pathology. Eur. J. Clin. Invest., 34: 785-796.
    PubMed
  187. Wong, T.Y., G. Liew, R.J. Tapp, M.I. Schmidt and J.J. Wang et al., 2008. Relation between fasting glucose and retinopathy for diagnosis of diabetes: Three population-based cross-sectional studies. Lancet, 371: 700-702.
    PubMed
  188. Wright, E.M., 1978. Transport processes in the formation of the cerebrospinal fluid. Rev. Physiol. Pharmacol., 83: 1-34.
    CrossRefDirect Link
  189. Yagihashi, S., S.I. Yamagishi and R.I. Wada, 2001. Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor. Brain, 124: 2448-2458.
    Direct Link
  190. Yen, V., 2010. Principles of Diabetes Mellitus. Part 8. Springer US, Canada, pp: 749-753.
  191. Young, B.A., C. Maynard and E.J. Boyko, 2003. Racial differences in diabetic nephropathy, cardiovascular disease, and mortality in a national population of veterans. Diabetes Care, 26: 2392-2399.
    CrossRef
  192. Zhang, D.X. and D.D. Gutterman, 2007. Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am. J. Physiol. Heart Circ Physiol., 292: 2023-2031.
    CrossRef

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