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Diabetes is a major threat to global public health, and the numbers of diabetic patients are rapidly increasing world-wide.  This study was aimed at determining the serum  electrolyte concentration and glycosylated haemoglobin level of diabetic patients and apparently healthy individuals.  A total of one hundred  and  twenty  (120)  subjects  were  used  for  the  study. Seventy (70) subjects (apparently healthy) aged between 38 and 60 years with no history of diabetes mellitus or any other hyperglycaemic disorder served as the control group while fifty (50) subjects of both genders (38-60 years) represented those with known history of diabetes mellitus . The subjects were divided into five (5) groups. Group 1 represents diabetic subjects with genotype  AA, group 2  represents  non-diabetic  subjects  with  genotype  AS, group 5 represents non diabetic  subjects with genotype SS, group 3 represents diabetic subjects on treatment with  genotype AA while group 4 represents diabetic subjects on treatment with genotype   AS.  All  subjects  used  were  residents   within  and  around   the  environs   of Gwagwalada,  Gwagwalada  Area  Council  of  the  Federal  Capital  Territory,  Abuja.  The duration  of the experiment  was two  (2) months.   Blood  samples  from  all  subjects were obtained by venipuncture from the anticubital vein into plain bottles. The blood was allowed to clot and then centrifuged for 10 min at 3000 rpm. The separated  serum was stored in a freezer  at  2-80C  till  the  time  of  use.  Whole  blood  for  determination  of  genotype  and glycosylated  haemoglobin  was obtained by venipuncture from the anticubital vein  into an EDTA container. The samples were kept in the refrigerator at 2–8 0c till the time of use. The result showed a significant decrease (p<0.05) in the serum sodium ion  (Na+) concentration of subjects in groups 3 and 4 representing  genotype AA diabetic  patients and genotype  AS diabetic patients compared  with the Na+  concentration  of group 1 subjects (AA  normal). Normal genotype SS individuals in group 5 exhibited non-significant increase (p>0.05) in the

Na+ concentration compared with that of AA and AS diabetic patients on treatment in groups 3 and 4. There was significant (p<0.05) elevation of the potassium ion (K+) concentration in groups 3, 4 and 5 which represented AA diabetic subjects on treatment, AS diabetic subjects on treatment and SS normal subjects respectively compared with the K+ concentration of  AA and AS normal subjects contained in groups1 and 2. The  chloride ion (Cl–) concentration decreased significantly (p<0.05) in AA and AS diabetic patients on treatment compared with AA, AS and SS normal subjects. However, non-significant (p>0.05) variations were observed in the Cl– concentration of AA, AS and SS normal subjects when compared with their AA, AS  diabetic  subjects  on  treatment.  Significant  decrease  (p<0.05)  was  observed  in  the bicarbonate  ion (HCO3–) concentration  of AA diabetic subjects on treatment,  AS  diabetic subjects on treatment and SS normal subjects compared with the HCO3– concentration of AA and  AS  normal  subjects.  The  level  of  glycosylated  hemoglobin  increased  significantly (p<0.05) in the AA and AS diabetic subjects on treatment compared with that of AA, AS and SS normal subjects. On the other hand, there was non-significant difference (p>0.05) in the level of glycated haemoglobin in AA, AS and SS normal subjects. It was observed from the result  of  the  present  study that  the  serum  electrolyte  (sodium,  potassium,  chloride  and bicarbonate)  and  glycosylated  haemoglobin  concentrations  showed  significant  difference (p<0.05) in accordance with diabetic mellitus patients irrespective of genotype. This could be utilized in the  management  of diabetic patients.  From this study, the predictive  value for glycosylated haemoglobin in diabetic patients can be said to be > 6.0 %.



Diabetes Mellitus (DM) is a group of metabolic  diseases characterized  by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both (Craig et al., 2009).  Diabetes  has  been  recognized  since  antiquity  and  its  symptoms,  which  include excessive drinking and frequent urination, were noted on Egyptian papyrus in about 1550 BC (later recognized by George Ebers) (MacFarlane  et al., 1997). The role  of the pancreas in diabetes was described in 1889 by Joseph von Mering and Oscar Minkowski (Von Mering and  Minkowski,  1889),  eventually  leading  to  the  discovery  of  insulin  in  1921  by  Sir Frederick Grant Banting and Charles Herbert Best (Banting et al., 1922); this changed the outcome  of diabetes  dramatically.  Before  the  discovery  of insulin,  patients  with Type  1 diabetes (T1D) became emaciated and  usually died within one or two years after diagnosis (Marks, 1965). The first patient was treated in 1922 and the New York Times declared that insulin could cure diabetes  (Tuchman,  2009). Mortality rates in patients  younger than 20 years declined dramatically a few years later (Patlak, 2002). However, with the introduction of insulin,  patients  lived  longer  and complications  became  more  apparent.  Renal  failure, cardiac   arrest,   blindness,   gangrene   and   other   complications   typically   shortened   life expectancy by 15 years (Patlak, 2002).

Until the 1950s, physicians did not distinguish between T1D and Type 2  diabetes (T2D). Still, they recognized a difference between what they called ―acute, and ―chronic (Tuchman, 2009). Insulin had a more dramatic effect on individuals with the ―acute form, which affected primarily young children. The chronic form tended to affect the middle-age, elderly obese and this form was insensitive to insulin. Currently, the ―acute form represents T1D and the chronic,  form represents  T2D. The World  Health Organization  suggested  a subdivision  of diabetes  into four main groups; T1D,  T2D, gestational  diabetes and other specific  types (heterogenic  group)  (WHO,  1999;  Soltesz  et al., 2006), the latter includes diabetes caused by genetic defects in beta-cell function, frequently called ―Maturity Onset of the Young (MODY), genetic defects in insulin action, genetic syndromes associated with diabetes and diabetes secondary to other conditions, such as pancreatitis and cystic fibrosis. Despite  increased  availability  of  insulin,  worldwide  mortality  is  not  declining  and  both prevalence  and incidence  appears  to be increasing.  Mortality  is an important  measure  of population  health  and   is  often  used  to  assign  priorities  in  health  interventions.  The International Diabetes Federation (IDF) (2010), estimated that four million deaths in the 20-

79 age groups may be attributable to diabetes in 2010, accounting for almost 7% of global mortality,   equal   to   many   infectious   diseases   like   Human   Immunodeficiency   Virus

(HIV)/Acquired  Immunodeficiency  Syndrome  (AIDS)  (Roglic  and Unwin,  2010).  Deaths attributable to diabetes in a global perspective have been challenging to estimate because one third of the countries of the world do not have reliable data. Most of these are countries in Sub-Saharan Africa (SSA) (Roglic et al., 2005). Routinely reported statistics based on death certificates  can  underestimate  mortality  by  threefold   because  individuals  often  die  of cardiovascular and renal disease and not from a cause directly related to diabetes (Roglic et al.,   2000).   Diabetes   is   increasing    most    rapidly   in   developing   countries,    where industrialization and urbanization have led to the adoption of a western lifestyle. According to WHO around 220 million people had diabetes in 2000 and the rate is predicted to double by 2030 (McKee, 2000).

1.2      Diabetes Mellitus

The  term  diabetes  mellitus  describes  a  metabolic  disorder  of  multiple  aetiology characterized  by chronic hyperglycemia  with disturbances of carbohydrate,  fat  and protein metabolism  resulting from defects in insulin secretion, insulin action,  or  both (Sundaram,

1996). Translated from Greek, diabetes mellitus means ‘honey sweet flow’ and this stemmed from a time in which tasting a patient’s urine was still part of the  physician’s diagnostic repertoire. The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs.

1.2.1    Symptoms of Diabetes Mellitus

Diabetes mellitus may present with symptoms  such as thirst, polyuria,  blurring  of vision and weight loss. In its most severe forms, ketoacidosis or a non-ketosis hyperosmolar state may develop and lead to stupor, coma and, in absence of effective  treatment, death. Often,  symptoms  are  not  severe,  or  may  be  absent,  and  consequently  hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the  diagnosis  is  made.  The  long-term  effects  of  diabetes  mellitus  include  progressive development   of   the   specific   complications   of   retinopathy   with   potential   blindness, nephropathy  that may lead to renal  failure, and / or neuropathy with risk of foot ulcers, amputation,  Charcot  joints,  and   features  of  autonomic  dysfunctions,   including  sexual dysfunction. People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular  disease  (Bonnefont  et al., 2000).  Several pathogenetic  processes  are involved in the development of diabetes. These include processes which destroy the beta cells of the  pancreas with consequent  insulin deficiency,  and others that result in resistance  to

insulin  action.  The abnormalities  of carbohydrate,  fat and  protein metabolism  are due  to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.

Diabetes has been reported to have significantly higher free radical activity as well as significantly   lower   concentrations   of   antioxidants,   compared   with   healthy   controls (Sundaram, 1996). In diabetic condition, persistent hyperglycaemia and hyperlipidemia cause increased production of free radicals especially reactive oxygen species, in all tissues from glucose  auto-oxidation  and  protein  glycosylation  (Aragno  et  al., 1999;  Bonnefont  et al., 2000). These changes are of greater magnitude in patients with disease complications than in those without disease complications. It is therefore possible that supplementing with nutrients and herbs that have antioxidant activity would help prevent diabetic gangrene and other organ damage (Sundaram, 1996). These radicals are generated as by-products of normal cellular metabolism.  However,  certain conditions  are known to  disturb  the balance between ROS production and cellular defense mechanisms.  The  imbalance can result in cell dysfunction and destruction resulting in tissue injury. The elevated levels of ROS in diabetics might be due to increased production of free radicals and or decreased destruction of free radicals by enzymatic  catalase, glutathione  peroxidase (GSH- px), and superoxidase  dismutase (SOD) antioxidants. The levels of these antioxidant enzymes critically influence the susceptibility of various tissues to oxidative stress and are associated with the development of complications in diabetes. The enzyme superoxide dismutase, glutathione peroxidase and catalase activity contribute   to  eliminate   superoxide   anions,   hydroxyl   radicals   and  hydrogen   peroxide respectively (Soto et al., 2003).

1.2.2    Blood Glucose Regulation

Fig.  1  showing  the  homeostatic   mechanism   which   keeps  the  blood   glucose concentration within a remarkable narrow range is composed of several interacting systems, of  which  hormonal  regulation  is  the  most  important.  There  are  two  types  of  mutually antagonistic metabolic hormones that are regulate blood  glucose  levels as shown in Fig. 1 below.  Catabolic  hormones  such  as  glucagon,  growth  hormone  e.g.  pituitary  hormone, glucocorticoid  e.g. cortisol, catecholamines e.g. adrenaline, noradrenaline,  dopamine which increases  blood  glucose;  while  anabolic  hormone  (insulin)  decreases  blood  glucose.  The human blood sugar level should be fairly constant at all times and this is made possible by the action of the two antagonistic hormones, insulin and glucagon. Both insulin and glucagon are secreted by the pancreas, and thus are referred to as pancreatic endocrine hormones. It is the production  of  insulin  and  glucagon  by the  pancreas  which  determines  if  a  patient  has diabetes, hypoglycemia or some other sugar metabolism related problem (John and  Henry, 2001).

The inducer of insulin secretion is high blood glucose. Although, there is always low level of insulin secreted by the pancreas, the amount secreted into the blood increases as the blood glucose rises. Similarly, as blood glucose falls, the amount of insulin secreted by the beta cells decreases.  Insulin has an effect on number of cells,  including muscle cells, red blood cells and fat cells. In response to insulin, these cells absorb glucose out of the blood, having the net effect of reducing the high blood glucose levels to the normal range (John and Henry, 2001). Glucagon is secreted by the alpha cells of the pancreas in the same pattern as insulin, but in opposing biochemical mechanism. If the blood glucose is high, no glucagon will be secreted. When blood glucose has decreased such as during period of fasting, more glucagon will be secreted. The effect of glucagon is to facilitate the release of glucose from the liver cells into the blood stream, with the net effect of increasing blood glucose. Glucagon also facilitates gluconeogenesis.

Fig. 1: The Regulation of Glucose. (Stephanie, 2008)

1.3      Classification of Diabetes

1.3.1    Type 1 Diabetes Mellitus

This  form  of diabetes  is also  called  insulin-dependent  diabetes,  and  results  from autoimmune mediated destruction of the beta cells of the pancreas (Zimmet et al., 1995). The rate of destruction of beta cells is quite variable, being rapid in some individuals and slow in others (Zimmet et al., 1994). The rapidly progressive form is commonly observed in children, but also may occur in adults (Humphery et al., 1998). The slowly progressive form generally form generally occurs in adults, and is sometimes referred to as latent autoimmune diabetes in adults (LADA). Some patients, particularly children and adolescents,  may present with ketoacidosis  as  the  first  manifestation  of  the  disease  (Japan  and  Pittsburgh  Childhood Diabetes Research Groups, 1985).

Individuals with Type 1 diabetes often become dependent on insulin for survival and are at risk of ketoacidosis (Wallins et al., 1996). At this stage of the disease, there is little or no insulin secretion as manifested by low or undetected levels of plasma C-peptide (Hother- Nielsen et al., 1988). Markers of immune destruction, like islet cell autoantibodies,  and/or autoantibodies  to  insulin,  and  autoantibodies  to  glutamic  acid  decarboxylase  (GAD)  are present  in  85-90%  of  individuals  with  Type  1  diabetes  mellitus  when  fasting  diabetic hyperglycaemia is initially detected (Verge et al., 1996). The peak incidence of this form of diabetes occurs in childhood to the ninth decade of  life (Molbak et al., 1994). There is a genetic  predisposition   to  autoimmune   destruction  of  beta  cells.  It  is  also  related  to environmental factors that are still poorly defined. Although, patients are usually not obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis.  These  patients may also have other autoimmune  disorders such as Graves’ disease, Hashimoto’s thyroiditis, and Addison’s disease (Betterle et al., 1983).  Epidemiology of  Diabetes  Interventions  and  Complication  Study  (EDIC)  reported  that  cardiovascular benefit was observed ten years after intensive treatment (Nathan et al., 2005); a 42% decrease in the cardiovascular rate and a 15 to 33% reduction in myocardial infarction in T1D subjects (Lillioja et al., 1993).

1.3.2    Type 2 Diabetes Mellitus

Diabetes mellitus of this type is regarded as non-insulin dependent diabetes, or adult- unset diabetes.  It is a term used  for individuals  who  have relative  (rather  than  absolute) insulin deficiency (Lillioja  et al., 1993). People with this type of diabetes  are frequently

resistant  to  the  action  of  insulin  (Lillioja  et  al.,  1993;  DeFronzo  et  al.,  1997).  These individuals  do not need  insulin treatment  to survive.  This form of diabetes  is  frequently undiagnosed  for  many  years  because  the  hyperglycaemia  is often  not  severe  enough  to provoke noticeable symptoms of diabetes (Harris, 1993; Mooy, et al., 1995). Nevertheless, such  patients   are  at  increased   risk  of  developing   macrovascular   and  microvascular complications  (Harris,  1993;  Mooy  et  al.,  1995).  There  are  probably  several  different mechanisms which result in this form of diabetes, and it is likely that the number of people in this category will decrease in the future as identification of specific pathogenetic processes and genetic defects permits better  differentiation  and a more definitive  classification  with movement into “Other types”.

Although,  the  specific  aetiologies  of  this  form  of  diabetes  are  not  known,  by definition autoimmune destruction of the pancreas does not occur and patients do not have other known specific causes of diabetes. The majority of patients do not have other known specific causes of diabetes. The majority of patients with this form of diabetes are obese; obesity itself causes or aggravates insulin resistance (Campbell and Carlson, 1993; Bogardus et al., 1985). Many of those who are not obese by traditional weight criteria may have an increased   percentage   of  body  fat  distributed   predominantly   in  the  abdominal  region (Kissebah et al., 1982). Ketoacidosis  is  infrequent  in this type of diabetes;  when seen it usually arises in association with stress of another illness such as infection (Banerji et al.,

1994; Umpierrez et al., 1995). Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the high blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their beta-cell function been normal  (Polonsky  et  al.,  1996).  Thus,  insulin  secretion  is  defective  and  insufficient  to compensate for the insulin resistance. On the other hand, some individuals have essentially normal insulin action, but markedly impaired  insulin  secretion. Insulin sensitivity may be increased by weight reduction, increased physical activity, and/or pharmacological treatment of hyperglycaemia but is not restored to normal (Simonson et al., 1984; Wing et al., 1994). The risk of developing Type 2  diabetes increases with age, obesity, and lack of physical activity (Zimmet, 1992). It occurs more frequently in women with prior gestational diabetes mellitus (GDM) and in individuals with hypertension or dyslipidaemia. Its frequency varies in different  racial/ethnic  subgroups (Valle et al., 1997). It is often associated  with strong familial,  likely genetic  predisposition.  However,  the genetics of this form of diabetes  are complex and not clearly defined. Some patients who present with a clinical picture consistent with Type 2 diabetes have autoantibodies similar to those found in Type 1 diabetes, and may

masquerade as Type 2 diabetes if antibody determinations are not made. Patients who  are non-obese or who have relatives with Type 1 diabetes and who are of northern Europe origin may  be  suspected   of  having   late  onset   Type   1  diabetes.   Individuals   with  chronic hyperglycaemia  insulin resistance,  and/or diabetes mellitus  Type 2 are of greater  risk for hypertension,  dyslipidemia,  and  cardiovascular  disease  (WHO,  2003).  Although  genetic factors may play a role in the  etiology of diabetes mellitus Type 2 (McCarthy, 2003), there is now convincing evidence that diabetes mellitus Type 2 is strongly associated with modifiable factors such as diet. Interestingly among the several factors present in diet, “coffee” one of the most widely consumed non-alcoholic beverages in western society (Keijzers et al., 2002), is highlighted as a potent dietary component associated with reduced risk of several chronic diseases, including diabetes mellitus Type 2 and its complications (Paynter et al., 2006). It is evident that early intensive glycemic control seems to reduce the risk of cardiovascular event later  in  life.  In the  last  two  years several  trials  among  T2D patients  (Patel,  2008)  have investigated if even more intensive glycemic control (HbA1c 6.4-6.9% compared to HbA1c

7.0-8.4%)  results in a further  reduction in cardiovascular  disease and mortality.  Intensive control did not seem to influence the outcome in short term (3 to 6 years after) when initiated in those  diagnosed  many  years  previously.  In one  study (Gerstein,  2008),  mortality did increase in the intensive treated group and because of the many hypoglycaemic episodes, this study was stopped after 3.5 years due to the rate of hypoglycaemic  episodes that was the cause of increased  mortality.  One suggestion  was  that less strict HbA1c goals than 7.0% might  be  indicated  for  patients  who  had  extensive  co-morbid  conditions,  limited  life expectancy, or an increased risk of severe hypoglycemia (Brown et al., 2010). Gestational Diabetes

Gestational  diabetes  is  carbohydrate  intolerance  resulting  in  hyperglycaemia  of variable severity with onset or first recognition during pregnancy (Kissebah et al., 1982). It does not exclude the possibility that the glucose intolerance may antedate pregnancy but has been previously unrecognized. The definition applies irrespective of whether or not insulin is used for treatment or the condition persists after pregnancy (Kissebah et al., 1982). Women who  become  pregnant  and  who  are  known  to  have  diabetes  mellitus  which  antedates pregnancy do not have gestational diabetes but have “diabetes mellitus and pregnancy” and should be treated accordingly before, during,  and  after the pregnancy. In the early part of pregnancy (e.g.  first trimester  and first  half of second  trimester)  fasting and postprandial glucose concentrations are normally lower than in normal, non-pregnant women (Polonsky et al., 1996). Elevated fasting or postprandial plasma glucose levels at this time in pregnancy

may well reflect the presence of diabetes which has antedated pregnancy,  but criteria  for designating abnormally high glucose concentration at this time have not yet been established (Polonsky et al., 1996). The occurrence of higher than usual plasma  glucose levels at this time of pregnancy mandates careful management and may be an indication for carrying out an OGTT. Nevertheless,  normal glucose tolerance in the  early part of pregnancy does not itself establish that gestational diabetes may not develop later. Individuals at high risk for gestational diabetes include older women, those with previous history of glucose intolerance, and those with a history of large for gestational babies, women from certain high-risk ethnic groups, and any pregnant woman who has elevated fasting, or casual, blood glucose levels. It may be appropriate to screen pregnant women belonging to high-risk populations during the first  trimester  of  pregnancy  in order  to  detect  previously  undiagnosed  diabetes  mellitus. Formal systematic testing for gestational diabetes is usually done between 24 and 28 weeks of gestation (Valle et al., 1997). Genetic defects of beta cell function

Several forms of the diabetic state may be associated with monogenic defects in beta- cell function which are frequently characterized by onset of mild hyperglycaemia at an early age (generally before age 25 years). They are usually inherited  in an autosomal dominant pattern (Byrne et al., 1960). Abnormalities  at three genetic loci on different chromosomes have  now  been  characterized.  The  most  common  form  is  associated  with  mutations  on chromosome  12  in  a  hepatic  nuclear  transcription  factor  referred  to  as  HNF1  alpha (Yamagata et al., 1996). A second form is associated with mutations in the glucokinase gene on chromosome 7p (Vionnet et al., 1992; Froguel et al., 1992).

Glucokinase  converts glucose  to glucose-6-phosphate,  the metabolism  of which  in turn stimulates insulin secretion by the beta cell. Thus, glucokinase serves as the  “glucose sensor” for the beta cell. Because of defects in the glucokinase  gene,  increased  levels of glucose are necessary to elicit normal levels of insulin secretion. A third form is associated with a mutation in the HNF alpha gene on chromosome 20q (Yamagata et al., 1996). HNF4 alpha is a transcription factor which is involved in the regulation of the expression of HNF alpha.  A  fourth  variant  has  recently  has  recently  been  ascribed  to  mutations  in another transcription  factor  gene,  IPF-1,  which  in its  homozygous  form  leads to total pancreatic agenesis  (Stoffers  et al., 1997). Specific  genetic  defects  in other  individuals  who  have a similar clinical presentation are  currently being defined. Point mutations  in mitochondrial DNA have been found to be  associated  with diabetes mellitus and deafness (Wagner  and

Turnbull, 1997). The most common mutation occurs at position 3243 in the  tRNAleucine gene, leading to an A to G substitution.

An  identical  lesion  occurs  in  the  MELAS  syndrome  (mitochondrial  myopathy, encephalopathy,  lactic acidosis, and stroke-like syndrome); however, diabetes is not part of this syndrome,  suggesting  for unknown reasons  different  phenotypic  expressions  of these genetic lesions (Johns, 1995). Genetic abnormalities  that result in  the inability to convert proinsulin to insulin have been identified in a few families. Such traits are usually inherited in an autosomal dominant pattern (Gruppuso et al., 1984; Robbins et al., 1984) and the resultant carbohydrate intolerance is mild. Similarly, mutant insulin molecules with impaired receptor binding have been identified  in a few  families.  These are also associated  with autosomal inheritance and either normal or  only mildly impaired carbohydrate  metabolism (Handa et al., 1984; Sanz et al., 1986).

1.4      Prevalence

In the past few decades significant increases have occurred in the pattern of health and diseases in many developing countries including Nigeria. The prevalence of diabetes in African  communities  is increasing  with  ageing  of  the  population  and  life  style  changes associated with rapid urbanization (Dod, 1989). As malnutrition and communicable disease come under control non communicable diseases like diabetes mellitus and hypertension have begun to emerge as major public health problems. Similar to the experience in many other parts  of  the  world,  diabetes  mellitus  is the  most  common  endocrine  metabolic  disorder encountered  in Nigeria  (Frings  et  al.,  1972).  Diabetes  mellitus  is  a major  global  health problem  and  it  has  an increasing  prevalence  due to  several  factors,  such as population, growth, aging, urbanization and increasing prevalence of obesity or lack of physical exercise. The  number  of  people  diagnosed  with  diabetes  is  increasing  at  an  alarming  rate.  It  is estimated that by the year 2030, 366 million people worldwide will have the disease (Chan et al., 2012).

1.5      Complications

Chronic hyperglycemia is associated with damage to small and large vessels, mainly affecting  the  cardiovascular  system,  the  kidneys,  the  retina  and  the  peripheral  nervous system. The Epidemiology of Diabetes Interventions and Complications Study (EDIC) was a follow up study of the DCCT, eight years after  intervention.  EDIC (Nathan et al., 2005) confirmed  the risk reduction for  microvascular complications  and provided  evidence  that intensive  diabetes  treatment  and  improved  glycemic  control  lead  to  a  significant  risk

reduction for macrovascular  complications  compared  to conventional treatment.  Clinically evident complications  are rare in childhood  and adolescence T1D; however,  abnormalities may be present a few years after onset of the disease. On the contrary, clinical presentation of T2D  is  often  slow  progressing   and  manifested   complications   such  as  dyslipidemia, hypertension.

Albuminuria may be present at diagnosis and should be assessed after blood glucose control has been optimized. In addition, complication testing at diagnosis should include eye examination,  liver enzymes  and control for obstructive  sleep  apnea.  Risk  factors  for the development of complications are longer duration of diabetes, older age, puberty, smoking, hypertension and family history of complications (Donaghue et al., 2009). In general, areas with specialized centres report a declining incidence of complications (Bojestig et al., 2011) and areas where health care is not optimal hold a greater risk of complications (Rossing et al.,

2002). However, this does not undermine the importance of good glycemic control.

1.5.1    Microvascular Complications

Microvascular  complications  include retinopathy,  nephropathy and neuropathy  and they are associated with a high degree of morbidity and mortality. Diabetic Retinopathy

In developed countries diabetic eye disease is among the leading cause of blindness and it is the fifth leading cause of global blindness, affecting an estimated 1.8 billion people (WHO, 2005). Diabetic retinopathy (DR) causes microvascular retinal changes and may lead to visual impairment and blindness. After 20 years of diabetes nearly all patients with T1D have  some  degree  of DR  (Skrivarhaug  et al., 2006).  Adolescents  have  a higher  risk of progression to vision threatening retinopathy compared with adults (Donaghue et al., 2009). Diabetic Nephropathy

Diabetic neuropathies are a heterogeneous group of disorders which can affect both the somatic and autonomic nervous system. Diabetic sensorimotoric polyneuropathy is the most common form and is often referred to as – diabetic neuropathy. Neuropathy can cause morbidity with significant impact on the quality of life of the person with diabetes, and can result in early death. The major morbidity is foot ulceration, which can lead to gangrene and ultimately to limb  loss.  Diabetic  neuropathy  is the most common  form of neuropathy  in developed countries and is responsible for 50 to 75% of non-traumatic amputations (Vinik et al., 2006).. A population survey (Harris and Eastman, 1993) reported that 30% of IDDM and

36  to  40%  of  non-insulin-dependent  diabetes  mellitus  (NIDDM)  patients  with  diabetes

experienced  neuropathic  symptoms.  It  is  expected  that  diabetic  neuropathy  is  grossly underdiagnosed and undertreated in many countries. Management of the disease is complex and the key to success depends, in part, on discovering the underlying pathological processes in each particular clinical presentation. There has been an increase in the understanding of the pathogenesis of diabetic neuropathies over the last decades and new therapies are emerging that hold promise for the treatment (Vinik et al., 2006).

Diabetic nephropathy (DN) is a major cause of morbidity and mortality among young adults with T1D. DN is characterized by progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is defined as persistent proteinuria  (greater than 500 mg/24 hours) or albuminuria (greater than 300 mg/24 hours) (Donaghue et al., 2009). The first clinical sign of progression to DN is microalbuminuria. Microalbuminuria is defined in one of three ways (Donaghue et al., 2009):

Albumin concentration 30–300 mg/L

Albumin excretion rate (AER) between 20 and 200 μg/min or AER 30–300 mg/24 hours in

24-hours urine collections

Albumin creatinine ratio (ACR) 2.5–25 mg/mmol or 30–300 mg/gm (spot urine)

Persistent microalbuminuria  and DN is associated with decreased glomerular filtration rate (GFR)  and indicates  progression  to end stage renal disease  (ESRD).  ESRD  is  the  prime indication for dialysis and kidney transplantation in many Western countries.  DN accounts for 25 to 30% of the patients with ESRD who require dialysis and it has been estimated that

30 to 40% of patients with IDDM will eventually develop ESRD (Selby et al., 1990). The process can be slowed by intensive treatment as shown in EDIC (Steffes et al., 2003). Only

6.8%    of    the    participants    in   the    previous    intensive-treatment    group    developed microalbuminuria and 1.4% developed clinical albuminuria, compared with 15.8% and 9.4% of participants in the previous conventional treated group. The total number of severe kidney events (kidney insufficiency) was more than three times greater  in the conventional treated group.

1.5.3    Macrovascular Complications

Macrovascular  complications  include  heart disease,  stroke  and peripheral  vascular disease (which can lead to ulcers, gangrene and amputation). Cardiovascular complications constitute the major cause of mortality in patients with T1D and T2D and life expectancy in T2D patients, diagnosed prior to the age of 40 years, is reduced by eight years relative to people without diabetes (Roper et al., 2001). Epidemiological studies have demonstrated that diabetes is an independent risk factor for cardiovascular disease and is associated with a two-

to fourfold increased  risk of coronary heart disease (Haffner et al., 1998). The  metabolic dysregulation  associated  with diabetes  mellitus  causes secondary  pathological changes  in multiple organ systems which imposes a tremendous burden on the individual with diabetes and on the health care system.

1.6      What Are Electrolytes?

Chemically, electrolytes are substances that become ions in solution and acquire the capacity to conduct electricity. Electrolytes are present in the human body, and the balance of the electrolytes in our bodies is essential for normal function of our cells  and our organs (Leonard and John, 1989). Common electrolytes that are measured with blood testing include sodium, potassium, chloride, and bicarbonate.

1.6.1    Sodium

Sodium  is the major positive  ion (cation)  in fluid outside  of cells.  The  chemical notation for sodium is Na+. When combined with chloride, the resulting substance is table salt. Excess sodium (such as that obtained from dietary sources) is  excreted  in the urine. Sodium regulates the total amount of water in the body and the transmission of sodium into

and out of individual cells also plays a role in critical body functions (Rao, 1992).  Many processes in the body, especially in the brain, nervous system, and muscles, require electrical signals  for  communication.  The  movement  of  sodium  is  critical  in  generation  of  these electrical signals. Therefore, too much or too little sodium can cause cells to malfunction, and extremes in the blood sodium levels (too much or too little) can be fatal. Increased sodium (hypernatremia)  in the blood occurs whenever there is  excess sodium in relation to water. There are numerous causes of hypernatremia;  these  may include kidney disease, too little water intake, and loss of water due to diarrhea and vomiting. A decreased concentration of sodium (hyponatremia) occurs whenever there is a relative increase in the amount of body water relative to sodium. This happens with some diseases of the liver and kidney, in patients with congestive heart failure, in burn victims, and in numerous other conditions.

A Normal blood sodium level is 135 – 145 milliEquivalents/liter (mEq/L), or in international units, 135 – 145 millimoles/liter (mmol/L).

1.6.2    Potassium

Potassium  is  the  major  positive  ion (cation)  found  inside  of  cells.  The  chemical notation  for potassium  is K+. The proper  level  of potassium  is essential  for  normal cell function. Among the many functions of potassium in the body are regulation of the heartbeat and the function of the muscles (Van, 1928). A seriously abnormal  increase in potassium

(hyperkalemia)  or decrease in potassium (hypokalemia)  can profoundly affect the  nervous system and increases the chance of irregular heartbeats (arrhythmias), which, when extreme, can be fatal. Increased potassium is known as hyperkalemia.

Potassium is normally excreted by the kidneys, so disorders that decrease the function of  the  kidneys  can  result  in  hyperkalemia.  Certain  medications  may also  predispose  an individual to hyperkalemia.  Hypokalemia, or decreased potassium, can arise due to kidney diseases;  excessive  loss  due  to  heavy  sweating,  vomiting,  or  diarrhea,  eating  disorders, certain  medications,  or  other  causes.  The  normal  blood  potassium  level  is  3.5  –  5.0 milliEquivalents/liter (mEq/L), or in international units, 3.5 – 5.0 millimoles/liter (mmol/L).

1.6.3    Chloride

Chloride is the major anion (negatively charged ion) found in the fluid outside of cells and in the blood. An anion is the negatively charged part of certain substances such as table salt (sodium chloride or NaCl) when dissolved  in liquid. Sea water has  almost  the same concentration of chloride ion as human body fluids. Chloride also plays a role in helping the body maintain a normal balance of fluids (Rao, 1992).

The  balance  of  chloride  ion  (Cl-)  is  closely  regulated  by  the  body.  Significant

increases or decreases in chloride can have deleterious or even fatal consequences: Increased chloride (hyperchloremia):  Elevations in chloride may be seen in diarrhea,  certain kidney diseases,  and  sometimes  in  over  activity  of  the  parathyroid  gland.  Decreased  chloride (hypochloremia):  Chloride  is  normally  lost  in the  urine,  sweat,  and  stomach  secretions. Excessive  loss  can occur  from  heavy sweating,  vomiting,  and adrenal  gland  and  kidney disease. The normal serum range for chloride is 98 – 108 mmol/L.

1.6.4    Bicarbonate

The bicarbonate ion acts as a buffer to maintain the normal levels of acidity (pH) in blood and other fluids in the body. Bicarbonate levels are measured to monitor the acidity of the blood and body fluids (Leonard  and John, 1989). The acidity is affected  by foods or medications that we ingest and the function of the kidneys and lungs. The chemical notation

for bicarbonate on most lab reports is HCO3-  or represented as the concentration of carbon

dioxide (CO2). The normal serum range for bicarbonate is 22-30 mmol/L. The bicarbonate test is usually performed  along with tests for other blood electrolytes.  Disruptions  in the normal bicarbonate  level may be due to diseases  that interfere  with  respiratory function, kidney diseases, metabolic conditions, or other causes.

1.7      Inter Relationship of Diabetes with Sodium- Potassium and ATPase

The  Na+,  K+-ATPase  (NKA)  is  an  ubiquitous  enzyme  consisting  of  α,  β  and  γ subunits, and is responsible for the creation and maintenance of the Na+  and K+  gradients across the cell membrane by transporting 3 Na+ out and 2 K+ into the cell (Suhail and Rizvi,

1990). Sodium pump regulation is tissue as well as isoform specific. Intracellular messengers differentially regulate the activity of the individual NKA isozymes.  Regulation of specific NKA  isozymes  gives  cells  the  ability  to  precisely  coordinate  NKA  activity  to  their physiological requirements (Reed et al., 2006). It is the only known receptor for the cardiac glycosides used to treat congestive heart failure and cardiac arrhythmias. Endogenous ligands structurally similar to cardiac glycosides may act as natural regulators of the sodium pump in heart and other tissues. Identification of naturally occurring regulators of  NKA could initiate the discovery  of  new  hormone-like  control  systems  involved  in the etiology of  selected disease processes,  hence the importance of understanding the relation of the sodium pump and its ligands to disease. Diabetes has a marked effect on the metabolism of a variety of tissues and  because the NKA is critical for the membrane potential and many transports, a change  in  its  activity  in  diabetes  would  have  profound  consequence  in  these  tissues (Kimelberg, 1975).

This is in contrast to the outside of the cell, where there is a high concentration of extracellular Na+ and a low concentration of extracellular K+. Thus, a concentration gradient exists  for  the  loss  and  gain  of  intracellular  K+   and  Na+,  respectively.  This  gradient  is maintained through the activity of various ionic channels and transporters, but predominantly

the activity of the NKA.  A typical  cell keeps a resting membrane  potential  of -70  mV. Potassium ions will tend to flow out of the cell, since their equilibrium potential (-91 mV) is more negative  than the trans membrane  potential.  Sodium ions have a  very strong force driving  them  into  the cell,  since  both the chemical  and  electrical  gradients  (equilibrium

potential of +64 mV) favor Na+ uptake. The enzymatic manifestation of the sodium pump is

the NKA. This enzyme, found in all mammalian cell membranes,  is necessary for  proper cellular function since it helps to preserve the ionic gradients across the cell membrane and thus the membrane potential and osmotic equilibrium  of the cell (Cox  et al., 2005). This function is crucial for cell survival and body homeostasis since the Na+  gradient is used as an

energy  source  to  transport  ions  or  solutes,  and  is  at  the  origin  of  the  vectorial  Na+ reabsorption  in  the  kidney  and  of  action  potentials  in  excitable  tissues.  It  is  putative component of a biological membrane that affects the transfer of these ions from one side of

the membrane to the other. It is active transport which is responsible for the well-established observation  that  cells  contain  relatively  high  concentrations  of  potassium  ions  but  low concentrations of sodium ions. The mechanism responsible for this is the sodium-potassium pump  which  moves  these  two  ions  in  opposite  directions across  the  plasma  membrane (Raccah et al., 1996). This was investigated by following the passage of radioactively labeled ions across the plasma membrane of  certain cells. It was found that the concentrations  of sodium  and potassium  ions on  the  two  other sides of the membrane  are interdependent, suggesting that the same carrier transports both ions. It is now known that the carrier is an ATPase and that it  pumps three sodium ions out of the cell for every two potassium ions

pumped in. It catalyzes the transfer of 2 K+ from the extracellular space into the cell and the

extrusion   of  3   Na+,   while   hydrolyzing   adenosine   triphosphate   (ATP)   to   adenosine diphosphate (ADP) and inorganic phosphate (Pi). The transport of 3 Na+ for 2 K+ across the membrane, through the means of the sodium pump, maintains trans membrane gradients for the ions and produces a convenient driving force for the  secondary transport of metabolic

substrates  such  as  amino  acids  and  glucose  (Suhail  and  Rizvi,  1990).  In  addition,  the nonequivalent  transport  is electrogenic  and  leads  to the generation  of a trans  membrane electrical  potential  allowing  cells  to  become  excitable.  The  “pump”  couples  the  energy released in the intracellular  hydrolysis of adenosine triphosphate  (ATP) to the transport of cellular ions, a major pathway for the controlled translocation of sodium and potassium ions across  the  cell  membrane.  NKA  therefore  controls  directly  or  indirectly  many  essential cellular  functions,  e.g. cell volume,  free calcium  concentration,  and membrane  potential. Regulation of this enzyme (transporter) and its individual isoforms is thought to play a key role in the etiology of some pathological processes (Cox et al., 2005)

1.7.1    Relevance in Diabetes Mellitus

Diabetes has a marked effect on the metabolism of a variety of tissues and because the NKA is critical for the membrane potential and many transports, a change in its activity in diabetes would have profound consequence in these tissues (Leonard and  John, 1989). We have observed significant effect of diabetes in the metabolism of diabetic erythrocytes and significant decrease in the activity of NKA in alloxan induced diabetic rats. Erythrocytes of diabetic patients have reduced life span, altered membrane dynamic properties and increased membrane thermo-stability (Knip et al., 2005). It has also been reported that diabetic patients with poor metabolic control have lower erythrocyte membrane enzymes activity as compared to healthy control subjects. The  modified proteins have altered functions such as modified enzymatic  activities,  lower  affinities  for  their  receptors.  Das  et  al.  (1976)  described  a

decrease of NKA enzyme activity in sciatic nerve of diabetic rat, whereas an increase  in enzyme  activity  was  found  in mucosa  of  the  small  intestine  of  diabetic  rat.  These two examples illustrate the different effect of diabetes on NKA depending on the tissues. Tissues can be classified in three groups, one principal group in which diabetes induces a decrease in NKA activity, including sciatic nerve, lens, heart, and erythrocyte; another group in which diabetes causes an increase in enzyme activity, including mucosa of the small intestine; and one group with a NKA activity unchanged  or where  it exists differences  between studies (Shoback et al., 2011).

Several mechanisms have been suggested to explain the decrease in NKA activity: a depletion  of the  intracellular  pool of myo-inositol,  an increased  flux  through  the  aldose reductase  pathway,  and an alteration  in protein  kinase-C  (PKC)  activity.  Other diabetes- induced  metabolic  changes  can  also  down-regulate  the  enzyme  activity,  including  the increase in oxidative stress, the formation of advanced glycation products, the nerve growth factor  metabolism,  and  the  disturbance  in  essential  fatty acid  metabolism  leading  to  an abnormal ω6/ω3 ratio in red blood cell membrane (Bluestone et al., 2010).

Moreover,  insulin and C-peptide deficiencies  can alter the long-term  regulation  of enzyme units expressed  at the cell surface.  The over-expression  of α isoforms  cannot be connected with an increase in enzyme activity; β isoforms are necessary to  form an active complex.   The   C-peptide   has   short-term   effect   or   NKA   activity   by   modifying   its phosphorylation  status.  Contrary  to  the  down-regulation  mechanisms,   the  mechanisms implicated  in  the  NKA  increase  in  some  tissues  of  diabetic  rat  seems  to  be  related  to variations  on mRNA  levels  of NKA  isoforms.  In  rat  skeletal  muscle,  insulin  is able  to produce a rapid translocation  of preexisting  NKA from intracellular  stores to the plasma membrane.  This results  in the  recruitment of additional  functional  Na pumps to  the cell surface and increased NKA activity.

The impairment of NKA activity, mainly secondary to the lack of C-peptide,  plays probably a role in the development of diabetic complications. The diabetes-induced decrease in enzyme activity would compromise micro-vascular blood flow by affecting micro-vascular regulation  and  decreasing  red  blood  cell  deformability,  which  lead  to  increased  blood viscosity  (Van  Style  and  Serdroy,  1928).  C-peptide  infusion   restored  red  blood  cell deformability and micro-vascular blood flow concomitantly with NKA activity. In 2000, the same  group  had  reported  that  insulin  and  C-peptide  directly  act  on  erythrocyte  NKA, restoring the decreased tissue NKA activity observed  in Type-1 diabetic patients. Low C- peptide level is considered  to be  responsible for low NKA activity in the red blood cells.

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