Oxidative Stress and Diabetic Nephropathy

Introduction

Diabetes mellitus is a chronic non-communicable condition resulting in high levels of glucose in the blood. It occurs due to inability of the beta cells in pancreas islet tissue to produce enough insulin, or when the body becomes resistant to insulin. It reduces both quality and length of life and over time leads to serious complications such as coronary heart disease, stroke, neuropathy, retinopathy and nephropathy.

There are two main types of diabetes mellitus:

Type 1 diabetes: also called insulin-dependent diabetes mellitus (IDDM), early-onset and juvenile diabetes. It is an autoimmune disease and results from destruction of insulin producing beta cells in islet tissues of pancreas by the body’s immune system. The subsequent lack of insulin results in high blood glucose levels, which if not controlled by exogenous insulin results in multiple organ damage.

Type 2 diabetes: formerly called non-insulin-dependent (NIDDM) and adult-onset. It is a metabolic disorder that mainly occurs in individuals over the age of 40. In this type of diabetes high blood glucose results either due to relative insulin deficiency or insulin resistance. Lifestyle and genetic factors play an important role in the development of type 2 diabetes.

Type 2 diabetes is a growing problem among the elderly population and is widely predicted to grow in the future. Since the population is aging in the western world, so it is not surprising that elderly population will contribute to future increase but other factors such as lifestyle and diet will also play a major role.

WHO survey 2010 estimated that 285 million of the world’s population have diabetes and more than 70% of them live in low and middle income countries. It is also estimated that this burden will increase to 438 million by 2030 (Diabetes fact, 2011). Wild 2004 projected that the total number of individuals with diabetes worldwide will increase from 171 million in 2000 to 366 million 2030. Although the prevalence of diabetes is higher in men compared to women but there are more women with diabetes than men. In developing countries type 2 diabetes mainly affects people of working age, between 35 and 64 years, whereas in developed countries the majority of people with diabetes are above the age of retirement i.e. above 65 years of age (WDD06 – Karachi, 2006). India has the largest diabetes world’s population i.e. 50.8 million followed by China with 43.2 million ( Express news report, 2009).

In Europe prevalence of clinically diagnosed diabetes was estimated to be 3% in 1997. It was estimated to increase to around 3.6% by 2000 and to over 4% by 2010 (Scottish Diabetes Survey 2003). In UK 4.26 % of population has diabetes according to the Diabetes UK statistics (Diabetes prevalence 2010). Scottish Diabetic Survey, 2010, projects that 4.6% of Scotland population has diabetes out of which 87.7% have type 2 diabetes.

Diabetes is also at an increase among children. Diabetes amongst children is primarily Type 1 diabetes but Type 2 diabetes is also increasingly being diagnosed. One of the major contributing factors for this rise in diabetes among children is the increase in the number of children who are overweight or obese. “Twenty five children in every 100,000 in Scotland have diabetes, compared to 17 in England and Wales.” An increase in this at a rate of 2% per years has been suggested by Diabetes UK in Scotland, as a result tripling of new cases in the last 30 years has been seen (ABPI Report Scotland, 2005).

Economic burden of Diabetes for families and society:

Diabetes and its complications have a significant economic impact on individuals, families, health systems and countries. For example, WHO estimates that in the period 2006-2015, China will need to allocate $558 billion in foregone national income due to heart disease, stroke and diabetes alone and India will spend $336.6 billion (Diabetes, 2011).

“In the poorest countries, people with diabetes and their families bear almost the whole cost of the medical care they can afford.” In Latin America, 40-60% of medical care expenditures is paid by the families themselves. In Mozambique, 75% of the per capita income is spent on diabetic care by one person; in Mali it amounts to 61%; Vietnam is 51% and Zambia 21%. It is estimated that poor people with diabetes in some developing countries spend as much as 25% of their annual income on private care (Diabetes fact. April 2011).

The trend of diabetes in developing countries show that it mostly affects working age group, between 35 and 64 years, relative to developed countries where the majority of diabetes population are aging. Therefore when principal wage earner is affected by diabetes and its complications, the choice between healthcare expenses and food or clothing can trap the whole family in a downward spiral of worsening poverty and health.

According to WHO, an annual 2% reduction in chronic disease death rates in Pakistan would provide an economic gain of 1 billion dollars over the next 10 years (WDD06 – Karachi, 2006). The cost incurred by diabetes morbidity are far greater than the cost of the disease prevention (Editorial in Lancet: World Diabetes Day 14th November, 2010).

In a press report by the independent economic consultancy group NERA it is assessed that intensive management of Type 2 diabetes in Scotland can decrease hospital cost by ?41 million by saving over 91,000 bed days a year in 2025 and will also save ?78 million a year in lost work days (ABPI Report Scotland, 2005).

Diabetic Nephropathy:

The diabetic complication, nephropathy is a condition with high unmet therapeutic needs. It is linked with significant increases in morbidity and mortality risk, and is the most common cause of ESRD in the Western countries. Diabetes-induced damage in the kidney leads to microalbuminuria. This progresses to ESRD, which requires dialysis or transplantation. Diabetes accounts for over 40% of ESRD (Diabetic Nephropathy, 2003).

The main focus of therapy in diabetic nephropathy is on tight control of blood pressure. Guidelines have progressively revised the target BP goal downwards, currently at 125/75 mmHg in patients with >1g proteinuria, and now recommend either ACE or ARB (Diabetic Nephropathy, 2003).

In the U.S., diabetic nephropathy accounts for about 40% of new cases of ESRD. In 1997 the cost required for treatment of diabetic patients having ESRD amounts to $15.6 billion. There is considerable racial/ethnic variability in this regard, Native Americans, Hipics (especially Mexican-Americans), and African-Americans have much higher risks of developing ESRD than non-Hipic whites with type 2 diabetes (Mark, 2001). In the UK, 1,000 people with diabetes start kidney dialysis every year. (Diabetes in the UK, 2004).

Ahmedani 2005 reports that in Karachi, Pakistan overall prevalence of microalbuminuria was found to be 34% in patients with diabetes and this was strongly associated with the age, diastolic hypertension, diabetic retinopathy and serum low density lipoprotein.

End stage renal disease is a most serious complication of diabetes and accounts to be the most expensive for NHS. Diabetic nephropathy usually develops 15-25 years after the occurrence of diabetes. In Scotland, 20% of patients who undergo renal transplantation are diabetic. In diabetic individuals, microalbuminuria and stroke, or an increased serum creatinine levels raises the risk of renal nephropathy and failure. Poor glycemic control and high blood pressure are risk factors of diabetic renal disease (Scottish Diabetes Framework, 2002).

Diabetic renal impairment is a strong indicator of Cardiovascular disease and cardiovascular disease is the major cause of morbidity and mortality is diabetic patients (Guillausseau, 2011). Annual cardiovascular mortality is 0.7% in normoalbuminuric patient as compared to 2% in microalbuminuric patients and 12% in the patient with elevated creatinine (Stratton IM, 2009)

In a review by Vishwanathan, 1999, it is explained that South Asians and Afro-Caribbean are more susceptible to develop renal disease relative to European. Retinopathy increases the risk of diabetic nephropathy. Prevalence of diabetic nephropathy in India was 30.3% in a study done among 4837 patients with chronic renal failure over a period of 10 years. He further argued that an increased prevalence of microalbuminurea among South Asians having type 2 diabetes mellitus relative to Europeans by 1.2 (men) and 1.7 (women) folds. According to SIGN 116, the incidence of diabetic nephropathy in patient with type 1 diabetes can be considerably reduced by attaining good glycaemic and tight blood pressure control. ­ In a report by Singh NP, 2003, it is suggested that the incidence of diabetic kidney disease can be reduced by: tight blood glucose control, blood pressure control, rennin-angiotensin-aldosterone system blockade and protein restriction.

Causes of microvascular damage in diabetes:

Long standing hyperglycemia lead to a number of damages including:

• Advanced glycosylated end products (AGES)
• Oxidative stress
• Increased sorbitol (polyol pathway)
• Increase in hexosamine pathway
• Impaired endothelial function
• Immune effect
• All these damages result in microvascular complications of diabetes.

Advanced glycosylated end-products (AGEs):

Chronic hyperglycemia causes increased glycosylation of proteins leading to AGEs, which in turn results in loss of structure and function, turning on/off signal pathways within cells and alteration in gene expression. AGEs are sugar-derived compounds, glucose binds amino groups on proteins, lipids and nucleic acids to form AGEs. AGEs form at a constant but slow rate throughout your life (even as an embryo) (Peppa et al, 2003).

AGEs interact with RAGE (surface AGE-binding receptors) resulting in proinflammatory effects, formation reactive oxygen species, loss of oxidants (oxidative stress) and altered gene transcription.

Levels of AGEs relates to extent of microvascular complications in diabetes. AGEs contributes to atheromatous plaque by stimulating low-density lipoprotein (LDL) oxidation and the deposition of oxidized LDL.

AGEs leads to endothelial dysfunction, macrophage activation, and impaired vascular smooth muscle cell function. Experimentally, AGEs cause glomerular damage and proteinuria.

Oxidative stress and Reactive Oxygen Species (ROS):

Oxidative stress is an imbalance between ROS production and antioxidants. Oxygen is used by cells to carry out their normal functions and as a side effect produces free radicals. Free radicals are missing an electron so are unstable and highly reactive. Free radicals steal electrons from molecules within cells causing oxidative damage to proteins, membranes and genes.

Polyol pathway/aldose reductase:

Aldose reductase (AR) normally reduces toxic aldehydes into inactive alcohols inside the cells. Glucose perfuses into some cells without insulin e.g. nerves. During hyperglycaemic condition, AR reduces that excess glucose to sorbitol (a polyol). Polyols are trapped inside the cells creating an osmotic gradient. Sodium and water flow into the cell resulting in oedema. But sorbitol can be metabolised to fructose by the actions of sorbitol dehydrogenase. High fructose leads to AGEs resulting in more cell damage (Takaqi et al, 1995).

Hexosamine pathway:

Glucose is mainly metabolised through glycolysis, some gets diverted into an alternative pathway, ending up as UDP (urine diphosphate) N-acetyl glucosamine. This alters transcription factors, often leading to pathologic changes in gene expression e.g. increased expression of transforming growth factor-B1 and plaminogen activator inhibitor-1, which damages blood vessels.

Endothelial dysfunction – pathogenesis:

Hyperglycemia leading to the formation of AGEs, ROS, the glycosylation of proteins and increased inflammatory cytokines etc. As a result small blood vessels, particularly the endothelium are damaged causing vasoconstriction, ischemia, and reduced flow to tissues that rely on the vessel for oxygen and nutrients.

Growth factors are also released leading to the blood vessel wall thickening and occlusion of small blood vessels. Nerve growth factors (NGF) and factors like it are damaged. These factors keep nerves healthy and capable of re-growth if damaged. Changes to the immune system lead to release of toxic cytokines, blockage of blood vessels with leukocytes and loss of normal immune cell action.

In this dissertation, a recent aspect of one of the above causes of microvascular damage of diabetes leading to nephropathy will be considered.

Current studies have uncovered new insights in the role of oxidative stress in diabetic renal disease, suggesting a different and innovative approach to a possible “casual” antioxidant therapy.

In this dissertation the role oxidative stress may play in the development of diabetic kidney disease will be discussed. The role of antioxidant therapy in managing or delaying the progression of diabetic nephropathy will be addressed.

References:  

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