Essay: Diabetes mellitus (DM), Type 2 Diabetes

Review of Literature
2.1 Definition and Classification
Diabetes mellitus (DM) is a group of metabolic disorders of heterogeneous etiology characterized by absolute or relative insulin deficiency leading to hyperglycemia and an altered metabolism of glucose, fat and protein (Pietropaolo et al., 2007; American Diabetes Association, 2014). The disease is classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes and other types of diabetes (American Diabetes Association, 2014). T1D and T2D are considered as the two major forms of DM. T1D normally develops before adulthood and is typically caused by an auto-immune destruction of the insulin-producing beta-cells leading to an absolute insulin deficiency, whereas T2D is normally associated with inadequate beta-cell response to the progressive insulin resistance (Kishida et al., 2012; Canivell and Gomis, 2014; Maganti et al., 2014). Gestational diabetes is defined as a state of glucose intolerance during pregnancy that usually subsides after delivery but has a major implication for subsequent risk of T2D (Philips et al., 2013). The other less common form of diabetes include genetic defects in insulin action, genetic defects in cell function, diseases of exocrine pancreas and drug or chemical induced diabetes (American Diabetes Association, 2014).
Figure 2.1: Criteria for the diagnosis of diabetes (Source: American Diabetes Association, 2014).
2.2 Genetics of T2D
T2D results from the complex interplay of many different pathways under the combined control of genetic, epigenetic and environmental factors (Doria et al., 2008; Prasad and Groop, 2015). The genetic component can be analyzed by comparing the risk of developing disease between relatives of patients with T2D and the background population, often referred to as sibling relative risk, which is around 3 in most populations (Lyssenko et al., 2005). High concordance rate obtained in monozygotic twins (96%) supports a substantial contribution of genetic factors to T2D (Kaprio et al., 1992; Medici et al., 1999). Furthermore the lifetime risk of developing T2D is 40% for individuals who have one parent with T2D and almost 70% if both parents are affected (Kobberling et al., 1982; Groop et al., 1996). The general estimates of heritability (h2) of T2D are 0.49 and the relative recurrence risk for a sib of an affected person (??s) to develop T2D is 3.5 (Risch, 1990; Lander and Schork, 1994). To date, approximately 70 susceptibility loci have been identified as being associated with T2D, among them 45 loci were identified in European populations and 29 loci were identified in Asian populations, especially in East and South Asians. However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D (Sun et al., 2014).
The involvement in the pathogenesis of T2D of multiple genes that interact with each other in an epistatic manner may explain why, despite the enormous efforts made to date, the identification of genetic determinants responsible for an increased susceptibility to T2D still remains unsolved (Doria et al., 2008; Ahlqvist et al., 2011). Genetic predisposition in T2D is also supported by the observation of differences in disease prevalence rates among populations, even after migration of entire ethnic groups to another country which indicates that this difference is independent from the environmental influences (Flegal et al., 1991). In Sweden, immigrants from the Middle East have a 2-3-fold increased risk of T2D compared to native Swedes. It is also more common for patients from the Middle East to have first-degree relatives with T2D (Glans et al., 2008). The role of environmental factors in influencing susceptibility to T2D is well known and among these factors are increased caloric intake and a sedentary lifestyle (Neel, 1962). The spread of the westernization in developing countries also explains the epidemic explosion of the disease (Wild et al., 2004; Danaei et al., 2011).
2.3 Epidemiology of T2D
As compared to the other two major types of diabetes, T2D is the most prevalent form and is responsible for 90% of the overall diabetes prevalence (Malecki, 2005; Lyssenko and Laakso, 2013). A global epidemic is predicted by World Health Organisation (WHO), with an estimated average increase in the prevalence of diabetes for all age groups from 2.8% in 2000 to 5.8% in 2030 (Wild et al., 2004). About 387 million people were estimated to have diabetes in the year 2014 and if these trends continue, by 2035, some 592 million people will have diabetes (International Diabetes Federation, 2014). Between 2010 and 2030, there is an expected 70% increase in numbers of adults with diabetes in developing countries and 20% increase in developed countries (Shaw et al., 2010). Almost half of all adults with diabetes are between the ages of 40 and 59 years and more than 80% people with diabetes in this age group live in low and middle income countries (International Diabetes Federation, 2013). Among the 10 countries with the largest numbers of people predicted to have diabetes mellitus in 2030, five are in Asia (China, India, Pakistan, Indonesia and Bangladesh) (Shaw et al., 2010).
Figure 2.2: Epidemiology of diabetes (Source: International Diabetes Federation, 2014).
As per report given by International Diabetes Federation (2013), India had 65.1 million people with diabetes and this number is predicted to increase by 109.0 million by 2035. In a study conducted by Indian Council of Medical Research’India Diabetes (ICMR-INDIAB), the prevalence of pre-diabetes and diabetes in Chandigarh was reported be 14.6% and 13.6%, respectively (Anjana et al., 2011). A study from India showed a significant increase in DM prevalence in both urban (from 13.9% in 2000 to 18.2% in 2006) and rural areas (from 6.4% in 2000 to 9.2% in 2006) (Ramachandran et al., 2008). The increasing worldwide prevalence of T2D combined with the shift in its age of onset will heavily burden health-care systems in the future. Similarly, for India the global burden of T2D by the year 2030 has been estimated to be 87 million (Snehalatha and Ramachandaran, 2009). In India age standardized prevalence of T2D was reported to be 12.1% (Ramachandran et al., 2001). The National Urban Diabetes Survey (NUDS) by Ramachandran et al. (2001), reported that T2D prevalence was higher in the Southern part of India (13.5% in chennai, 12.4%, in Bangalore and 16.6% Hyderabad) as compared to Eastern (11.7% in Kolkatta), Northern (11.6% in New Delhi) and Western India (9.3% in Mumbai). T2D prevalence was three times higher among the urban population (8.2%) as compared to the rural population (2.4%) (Ramachandran et al., 1992). The prevalence of T2D across different cities has been depicted in Table 2.2.
Table 2.1. Prevalence of diabetes in India
Place Prevalence (%) Area Author
Kashmir 6.05 Northern Ahmad et al., 2011
New Delhi 15.0 Northern Prabhakaran et al., 2005
Jammu 8.15 Northern Shora et al., 2014
Punjab 4.6 Northern Wander et al., 1994
Chandigarh 13.6 Northern Anjana et al., 2011
Mumbai 9.3 Western Ramachandran et al., 2001
Jaipur 12.1 Western Gupta et al., 2004
Nagpur 3.2 Western Mohan et al., 2008
Manipur 4.0 Eastern Singh et al., 2001
Assam 8.2 Eastern Shah et al., 1999
Kolkata 11.5 Eastern Kumar et al., 2008
Chennai 18.6 Southern Ramachandran et al., 2008
Kochi 19.5 Southern Menon et al., 2006
Kerala 27.11 Southern Jose et al., 2013
Bangalore 10.7 Southern Ajay et al., 2008
Hyderabad 14.1 Southern Ajay et al., 2008
2.4 Pathophysiology of T2D
T2D is characterized by the combination of disturbances in insulin secretion by pancreatic ??-cells and peripheral insulin resistance, which is often related to obesity (Guja et al., 2012). Insulin resistance is caused by defects in the signaling pathways that process the insulin signal in its target tissues (Wolfs et al., 2009). Normally, plasma glucose levels are maintained within a narrow and well-balanced range, known as glucose homeostasis (Baynes and Dominiczak, 2004). However, as a consequence of impaired insulin secretion and resistance, glucose uptake and release by pivotal tissues is disturbed which eventually leads to hyperglycemia (DeFronzo, 2004; DeFronzo and Tripathy, 2009). It has often been suggested that the disease starts with insulin resistance and is followed by increased insulin production by the pancreatic ??-cells to maintain glucose homeostasis (Weir and Bonner-Weir, 2004). At a later stage, due to the long-term compensation mechanism by the ??-cells to keep up with the higher insulin demand, these cells ultimately undergo further damage and apoptosis (Prentki and Nolan, 2006). When the ultimate demand of insulin release cannot be satisfied, higher plasma glucose levels are the result. The vulnerability of the ??-cell pool in insulin-resistant conditions is determined by problems related to ??-cell survival, ??-cell regeneration, or ??-cell development which are involved in the insulin secretion pathways (Kahn, 2003; Wolfs et al., 2009).
Figure 2.3: Pathophysiology of T2D (Source: Inzucchi and Sherwin, 2011).
It has been shown that although obesity is a major risk factor for diabetes (around 50% of the patients with diabetes are obese), a significant proportion of T2D are not obese (Pimenta et al., 1995). Therefore, it has been concluded that obesity may be a major risk factor for T2D development but it is the vulnerability of the ??-cell pool which determines whether obesity triggers the development of T2D or not (McCarthy, 2010).
2.5 T2D and its Complications
The increasing prevalence of T2D represents a significant burden to human health because of its numerous and often serious complications (Mohan et al., 2013). These complications of T2D are divided into macrovascular and microvascular complications (Cade, 2008). Macrovascular diseases include coronary artery disease (CAD), peripheral vascular disease, and atherosclerosisis (Papa et al., 2013). Microvascular complications occur mainly in the eyes, kidneys, peripheral lower limbs and nerves, resulting in diabetic retinopathy, diabetic nephropathy, diabetic foot and diabetic neuropathy, respectively (Fowler, 2008). These complications lead to reduced quality of life and increased morbidity and mortality from end-stage renal disease (ESRD) and cardiovascular disease (CVD) (Van Dieren et al., 2010) The chronic hyperglycemia plays a central role in the development and progression of the vascular complications, which often persist and progress despite improved glucose control, possibly as a result of prior occurrences of hyperglycemia (American Diabetes Association, 2014). Prospective randomized clinical trials and epidemiological studies have shown that glycemic control is interrelated with reduced rates of retinopathy, nephropathy, neuropathy and cardiovascular diseases and considered as the main therapeutic goal for the prevention of complications of diabetes (Middleton, 2003; American Diabetes Association, 2013).
Figure 2.4: Complication of Diabetes (Source: International Diabetes Federation, 2014).
2.6 Diabetic Nephropathy (DN)
DN is a multifactorial disorder caused by hyperglycemia-induced renal damage in genetically predisposed patients (Savage and Maxwell, 2009). It is the leading cause of ESRD (Yacoub and Campbell, 2015). DN refers to a characteristic set of structural and functional kidney abnormalities in patients with diabetes (Kanwar et al., 2011). The structural abnormalities include hypertrophy of the kidney, increase in glomerular basement membrane (GBM) thickness, nodular and diffuse glomerulosclerosis, tubular atrophy, and interstitial fibrosis (Kimmestiel and Wilson, 1936; Alebiosu et al., 2002; Tervaert et al., 2010). The functional alterations include an early increase in glomerular filtration rate (GFR) with intraglomerular hypertension, subsequent proteinuria, systemic hypertension, and eventual loss of renal function (Hostetter et al., 1982; Fioretto and Mauer, 2007)
2.6.1 Stages of DN
Based on the GFR decline, renal physiology and albumin excretion progression of DN has been classified into five different stages as suggested by Mogensen et al. (1983).
Table 2.2. Different stages of diabetic nephropathy
Designation Characteristics GFR
(ml/min/1.73m2) Albumin Excretion Chronology
Stage 1 Hyperfunction and hypertrophy Glomerular Hyperfiltration >90 May be increased Present at the time of diagnosis
Stage 2 Silent stage Thickened GBM Expanded mesangium 60-90 < 200 mg/dl First five years Stage 3 Incipient stage Microalbuminuria 30-59 30-300 mg/dl 6-15 years Stage 4 Overt diabetic nephropathy Macroalbuminuria 15-29 > 380 mg/dl 15-25 years
Stage 5 Uremic ESRD <15/dialysis Decreasing 25-30 years 2.7 Epidemiology of DN DN is one of the most common complications of T2D affecting up to 30% of patients. (Wu et al., 2010; Lv et al., 2015). DN is leading cause of chronic kidney disease, resulting in ESRD; thus profoundly contributing to patient morbidity and mortality (Savage and Maxwell, 2009). Asian patients have shown evidence of macro and micro vascular disease at the time of diagnosis of diabetes when compared to European population (Chowdhury and Lasker et al., 2002). In chronic renal failure patients the prevalence of DN was 30.3% followed by chronic interstitial nephritis (23%) and chronic glomerulonephritis (17.7%) (Ramachandran, 2007). In Australia, the number of patients with T2D starting dialysis increased fivefold between 1993 and 2007 (McDonald et al., 2008). In Japan, between 1983 and 2005, the increase was sevenfold, and patients with diabetes accounted for 40% of new cases receiving dialysis. A study by Parving et al. (2006) which involved 33 countries, 39% T2D cases had microalbuminuria and its prevalence increased with age, duration of diabetes and presence of hypertension. The prevalence of overall DN among T2D cases from Egypt, Taiwan, Thailand and Saudi Arab was reported to be 47%, 40%, 37.2% and 10.8%, respectively (Shen et al., 2009; Krairittichai et al., 2011; Al-Rubeaan et al., 2014; Farahat et al., 2014). In Indian population DN accounted for 44% new ESRD cases (Modi and Jha, 2006). The annual incidence of ESRD in India was reported to be 150-200 per million population, which appears to be lower than ESRD registries reported from developed countries (Agarwal and Srivastava, 2009). In urban Asian Indians, the prevalence of overt nephropathy and microalbuminuria was 2.2% and 26.9%, respectively (Unnikrishnan et al., 2007). The prevalence of DN in different parts of India is given in Table 2.3 Table 2.3. Prevalence of DN among T2D cases in India Place Prevalence (%) Area Author New Delhi 25.5 (microalbuminuria) Northern Kanakamani et al., 2010 Chennai 36.3 (microalbuminuria) Southern Varghese et al., 2007 Kolar 37.02 Southern Reddy et al., 2012 Vadodara 28.4 (microalbuminuria) Western Venugopal and Iyer, 2010 Bikaner 32.5 Western Agrawal et al., 2004 Bhuj 28.33 (microalbuminuria) Western Parchwani and Singh, 2011 Pune 23.0 Western Yajnik et al., 1992 2.8 Risk factors for DN in T2D DN is one of the major microangiopathies of DM, occurring in approximately 30% of T2D patients. The pathogenesis of DN is not yet clearly understood, but available data suggest that multiple factors contribute to this complication (Chowdhury et al., 1999). The development and progression in T2D towards DN involve but are not limited to the following risk factors (Jin and Patti, 2009; Viswanathan et al., 2012). Genetic Predisposition Genetic predisposition plays an important role in pathogenesis of DN. Studies of familial aggregation has showed that the diabetic sibling of a patient with DN has a three-fold greater risk of DN than the diabetic sibling of diabetes without nephropathy (Loon, 2003). A study by Seaquist et al. (1989) reported that 83% of T2D siblings of DN patients have evidence of renal disease. Another study on 310 families comprising 662 patients with T2D found heritability of 0.35 for UAE and of 0.69 for GFR (Langefeld et al. 2004). These findings were similar to those described in other studies reporting a heritability of creatinine depuration of 0.63 among mono- and dizygotic twins (Hunter et al., 2002). Hyperglycemia Hyperglycemia is considered to induce renal damage directly or through hemodynamic modifications (Schena and Gesualdo, 2005). Diabetes Control and Complications Trial (DCCT) studies have shown that improved metabolic control is associated with decreased development and progression of nephropathy in diabetes (DCCT, 1993). This is supported by the studies, which showed that the risk of development and progression of albuminuria could be substantially reduced by improving glycemic control (Zelmanovitz et al., 2009). A reduction of 1% in HbA1c is associated with a 37% decrease in microvascular endpoints (Stratton et al., 2000). In the presence of micro- and macroalbuminuria the role of metabolic control is less defined, even though some studies showed a deleterious effect of high glucose levels on GFR (Alaveras et al., 1997; Hovind et al., 2003). Obesity Obesity has been identified as well known risk factor for DN in T2D. Obesity has been considered as an independent risk factor, not only if it is present, but also if it was present in the past. This observation indicated that even history of obesity has a legacy effect on T2D patients which increases their risk towards progression to nephropathy (Meguro et al., 2013). A study by Ejerblad et al. (2006), suggested that obesity anytime during lifetime was linked to three- to four-fold increases in diabetic chronic renal failure risk. Another study by Chen et al. (2013) also found strong association between obesity in the earlier stages and increased risk of proteinuria. Hypertension Hypertension is probably the best known relevant factor related to DN progression. The etiology of hypertension in DN involves mechanisms with multiple inter-related mediators that result in renal sodium reabsorption and peripheral vasoconstriction (Van Buren and Toto, 2011). Analysis of UKPDS showed that every 10 mmHg reduction in SBP is associated with a 13% reduction in the risk of microvascular complications, with the smallest risk among those patients with SBP <120 mmHg (Adler et al., 2000). The presence of hypertension in the diabetic population is 1.5 to 3 times higher than in a non-diabetic, age-matched group (Arauz-Pacheco et al., 2002). Previous prospective and case control studies also have shown that hypertension progression is an independent predictor of T2D and DN (Kumari et al., 2004; Conen et al., 2007; Unnikrishnan et al., 2007; Movahed et al., 2010; Priya et al., 2013). Dyslipidemia Dyslipidemia has been identified as a key risk factor for development and progression of DN in T2D (Jisieike-Onuigbo et al., 2011). The levels of cholesterol both at onset and after a five-year followup period were positively related with the subsequent increase in UAE in microalbuminuric patients with T2D (Ravid et al., 1998). The association of low High density lipoprotein (HDL)-cholesterol and high plasma triglycerides levels with risk of T2D and DN have been documented in several studies (Rutledge et al., 2010; Morton et al., 2012). Cross sectional studies have also shown that hyperglycemia is associated with higher levels of total cholesterol and triglycerides and lower concentrations of HDL-cholesterol (Tsai et al., 2004; Mahajan et al., 2013; Sikka et al., 2014) Proteinuria Increased urinary albumin is a key component of DN. Its development leads to increased mortality and morbidity for diabetic ESRD patients in comparison to non-diabetic ESRD cases (Campbell et al., 2003). Proteinuria itself could lead to progression of DN, and levels more than 2g/24h is often associated with a greater risk of ESRD (Ruggenenti and Remuzzi, 1998). Reduction in albuminuria levels have also been seen to slow the progression of diabetic kidney disease and improve clinical outcomes, even in normotensive patients (Kidney Disease Outcomes Quality Initiative, 2007). Smoking Smoking in diabetic patients with vascular complications produces a variety of pathological changes in the kidney, such as thickening of the GBM, mesangial expansion, progression in glomerulosclerosis and interstitial fibrosis, which ultimately results in ESRD (Hua et al., 2010; Chakkarwar, 2012). It has been demonstrated that nicotine, one of the compounds present in large amounts in tobacco, promotes mesangial cell proliferation and fibronectin production (Obert et al., 2011). Although some studies did not confirm these observations, but it is strongly recommended to quit smoking in any phase of DN, also aiming to reduce the associated cardiovascular and cancer risk (Gall et al., 1997; Hovind et al., 2003; Zelmanovitz et al., 2009). A study by Unnikrishnan et al. (2007) in South Indian also suggested smoking as an important risk factor for DN progression. Dietary factors An important life style factor associated with the development of T2D and DN is dietary habits (Liese et al., 2009). Positive association have been reported between the risk of DN and different patterns of food intake (Van Dam et al., 2002). In patients with T2D, it was observed that the presence of microalbuminuria was associated with the lower content of polyunsaturated fatty acids, especially those of vegetal origin (Almeida et al., 2008). A review which included 19 studies, concluded that a higher intake of polyunsaturated fat and long-chain n.3 fatty acid is beneficial, where as higher intake of saturated fat and trans-fat adversely affects glucose metabolism and insulin resistance (Hu et al., 2001). Ethinicity Ethinic background lays an important role because some races are more susceptible to DN than others. The rate of developing ESRD is five times higher in relatives of black patients with T2D (Freedman et al., 1993). The incidence and severity of DN is higher in blacks, Mexican Americans, Pima Indians, and Hispanics as compared to Caucasians (Pugh et al., 1998; Ritz and Orth, 1999). This racial difference may be caused by specific clustering of different loci, which induces genetic susceptibility to the disease (Schena and Gesualdo, 2005). Male Gender Insight from in vitro studies and animal models suggest that sex steroids play pivotal roles in modifying the progression to ESRD (Yanes et al., 2008). Male gender considered to be an independent risk factor for development and progression of incipient and overt DN (Gall et al., 1995). Men progress to ESRD faster than postmenopausal women (Yanes et al., 2008). A study by Bamashmoos and Ganem (2013), reported that DN was more prevalent in males than females. Another prospective observational study involving 176 patients with T2D, found that males had a 2.6 times greater risk of developing incipient or overt nephropathy (Gall et al., 1997). Similar observation was made in North Indian population where higher percentage of males were affected with DN (Mittal and Manchanda, 2007; Tiwari et al., 2009). These gender differences could be attributed to nephroprotective effects of female hormones especially the estrogen (Gluhovschi et al., 2012). Glomerular hyperfiltration Elevated GFR values are present in about one third of T2D patients and theoretically it could cause DN due to glomerular damage (Silveiro et al., 1993; Brenner et al., 1996; Ito et al., 2010). Studies led to controversial findings regarding its role as a risk factor for the development of DN (Murussi et al, 2002). Glomerular hyperfiltration probably plays a small role, if any, in the development of DN (Yip et al., 1996). 2.9 Pathophysiology of DN The pathophysiological mechanisms in the development of DN are multifactorial. DN has several distinct phases of development and multiple mechanisms that contribute to the development of the disease and its outcomes (Dronavalli et al., 2008). Hyperglycemia is the initiating event which causes structural and functional changes, followed by the development of GBM thickening, accumulation of mesengial matrix and overt proteinuria and finally glomerulosclerosis and ESRD (Vinod, 2012). The pathophysiological mechanisms of DN can be further divided into hemodynamic and metabolic factors. Figure 2.5: Pathways involved in diabetic kidney disease (Souce: Vinod et al., 2012 and Kanwar et al., 2011). 2.9.1 Metabolic Factors Prolonged hyperglycemia in diabetic patients is the root cause of all microvascular complications which develop at the later stage of the disease (Campos, 2012). Clinical studies such as Diabetes Control and Complication Trial (DCCT) and UK Prospective Diabetes Study (UKPDS) have shown that intensive glycemic control retards the progression and development of microalbuminuria and overt nephropathy (Adler et al., 2000; Kelly et al., 2003). However, achieving and maintaining normal blood glucose levels in diabetic patients still remains a challenge. High glucose induced upregulation of angiotensin II (Ang II) production and several other growth factors such as transforming growth factor beta (TGF-??), vascular endothelial growth factor (VEGF) in mesangial cells and in proximal tubular cells has been confirmed in in-vitro studies (Hsieh et al., 2002). In addition high glucose induces the production of superoxide by the mitochondrial electron transport chain, can activate nuclear factor kappa B (NF-??B) through the stimulation of protein kinase C (PKC) activity in endothelial cells, thus contributing to the progression and development of DN (Nishikawa et al., 2000). Advanced glycation end products (AGEs) Sustained hyperglycemia leads to non-enzymatic glycation resulting in Amadori's products known as advanced glycation end products (AGEs). Once formed, the reaction is not reversible, and it gradually accumulates over the lifetime of the protein (Tan et al., 2007). AGEs can modulate cellular functions by interacting with their cognate receptor, RAGE (receptor for AGEs) (Kanwar et al., 2011). AGEs are known to be one of the major contributors in the progression of DN and other complications associated with diabetes (Gugliucci and Bendayan, 1995). AGEs are produced in small amounts under normal physiological conditions but their levels markedly increase in a chronic hyperglycemic milieu (Jakus and Rietbrock, 2004). Almost all renal structures are susceptible to accumulate AGEs including basement membranes, mesangial and endothelial cells, podocytes and renal tubules (Busch et al., 2010). Accumulation of AGEs such as N-??-carboxymethyllysine (CML) and pentosidine in the kidney leads to the progressive alteration in renal structure and loss of renal function that is seen in long-term diabetes in humans and rodents (Huebschmann et al., 2006). There are several studies confirming inhibition of AGE formation prevents the development and progression of experimental DN (Fukami et al., 2007). AGEs have been also reported to induce apoptotic cell death, VEGF stimulation, activation of TGF-??-Smad signaling pathways and Monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells (Yamagishi et al., 2002). Figure 2.6: Sequence of events following AGE-RAGE interaction and increased PKC activity (Source: Kanwar et al., 2011). Protein Kinase C (PKC) pathway Activation PKC results in a myriad of potential harmful effects related to diabetic complications (Geraldes and King, 2010). In cultured vascular cells, elevated glucose concentrations primarily activate the ?? and ?? isoforms of PKC (Way et al., 2001). In DN, hyperglycaemic environment induces increased PKC-??2 activity in renal endothelial cells to produce prostaglandin E2 and thromboxane A2, substances that alter the permeability and the response to angiotensin of vascular cells (Geraldes and King, 2010). The mechanism by which hyperglycemia leads to PKC activation involves de novo formation of diacylglycerol (DAG) and oxidative stress (Luis-Rodr??guez et al., 2012). The activation of this enzyme leads to increased secretion of vasodilatory prostanoids, which contributes to glomerular hyperfiltration (Yamagishi et al., 2002). The over activity of PKC has been implicated in the decreased nitric oxide (NO) production in smooth muscle cells and has been shown to inhibit insulin-stimulated expression of endothelial NO synthase (eNOS) in cultured endothelial cells (Way et al., 2001; Luis-Rodr??guez et al., 2012). In addition to alterations of blood flow and permeability, activation of PKC also contributes to the accumulation of micro vascular matrix protein by inducing expression of TGF-??, fibronectin and type IV collagen in both cultured mesangial cells and in experimental animal models (Weigert et al., 2004). Oxidative stress Growing evidence indicates that metabolic abnormalities in diabetes leads to increase in oxidative stress and the overproduction of reactive oxygen species (ROS) (Giacco and Brownlee, 2010). This ROS production results in the activation of major biochemical harmful pathways, including increased AGE formation, activation of protein kinase C, increased flux through the polyol pathway, and over activity of the hexosamine pathway, each of which, in addition, can initiate and perpetuate cellular ROS generation (Vasavada and Agarwal, 2005; Forbes et al., 2008). The ability of individual cell types to process glucose is the most important factor in the excessive intracellular generation of ROS induced by hyperglycemia (Elmarakby and Sulliva, 2010). Thus, the control of glucose influx into the cytosol in presence of elevated glucose concentrations is critical in order to maintain an adequate intracellular glucose homeostasis (Luis-Rodr??guez et al., 2012). However, certain renal cell populations, such as endothelial, mesengial, epithelial and tubular cells, are particularly susceptible since they are unable to decrease glucose transport rates adequately. Therefore, intensive glycemic control and interventions that decrease cellular glucose uptake may limit ROS generation in the diabetic kidney (Hayden et al., 2005). Aldose Reductase (Polyol) pathway When intracellular glucose levels are increased, the polyol pathway of glucose metabolism becomes active (Luis-Rodr??guez et al., 2012). The first and rate-limiting enzyme in this pathway is aldose reductase, which reduces glucose to sorbitol using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor; sorbitol is then metabolized to fructose by sorbitol dehydrogenase that uses nicotinamide adenine dinucleotide (NAD+) as a cofactor (Ramana et al., 2005). The polyol pathway is activated under hyperglycemic conditions, and is considered to play an important role in the development of DN (Iso et al., 2001). Intracellular sorbitol accumulation and decline in NADPH contents caused by increased AR flux has been postulated to induce osmotic damage and oxidative stress, respectively (Chung et al., 2003). Activation of aldose reductase enzyme itself is able to cause damage, as well as through other mechanisms such as activation of PKC and protein glycosylation (Haneda et al., 2003). Some studies have shown that the inhibition of aldose reductase may have a beneficial effect on proteinuria and GFR (Chu

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