Abdulrahman Al-Ajlan, Ph.D
Clinical Biochemistry Department
Riyadh College of Health Sciences, (Men)
King Saud University - Riyadh. KSA.

Correspondence:
Dr. Abdulrahman Al-Ajlan
Clinical Biochemistry Department
Riyadh College of Health Sciences (Men)
King Saud University, P.O. Box 22637
Riyadh 11416, KSA
Tel: 01 - 4484964
Fax: 01 - 4481033
Email: aalajl@hotmail.com

INTRODUCTION

Diabetes is one of the most dangerous consequences of our modern civilization.¹ Decrease in physical activity, increased life span and the world's growing population of obese are among the new factors that aggravate the problem^2-5.
With 10% of total health care expenditure in many countries millions of families will be left to struggle with emotional and financial burden of this debilitating disease^2,6.
A concerted effort of all governments is required to face the challenge by firm commitment to fight this threat through the establishment of diabetic research centers and national institutions².
It was observed that diabetes grows faster in developing countries, for example India has the world's largest diabetic population, where 25% of a family's income is consumed on diabetic care^2,6.
Obstacles to treatment and prevention in this case include the lack of well-trained medical personnel, undiagnosed cases, decreased insulin stocks, and lack of coordination. The economic cost of the problem and its complications are enormous for the health care systems. The loss of productivity is also the price to be paid⁶.
Knowledge regarding etiology and pathogenesis needs revision of the criteria for early diagnosis, testing, and classification, since management of diabetes depends on these parameters. Education is another cornerstone in this battle. Preventing complications and further disability can be achieved by self-management and educating the diabetic patient. Gathering data and analyzing information from individuals and organizations in this field and the feedback about patient satisfaction may prove to be of great importance².

Definition and Description of Diabetes Mellitus:
It is a group of metabolic disorders of multiple etiologies characterized by chronic hyperglycemia with disturbance of carbohydrate, fat, and protein metabolism resulting from a defect in insulin secretion or action, or both^3,8,9,10. Hyperglycemia is usually associated with long term damage, dysfunction or even failure of various organs especially the eyes, kidneys, nerves, heart and blood vessels^3,11.
There is an increasing tendency to consider diabetes mellitus as a part of metabolic syndrome. The people known to suffer from metabolic syndrome are at a higher risk of complications. It is well documented that the features of the metabolic syndrome can be present up to ten years before detection of hyperglycemia. Now evidence is accumulating that even people with metabolic syndrome and normal glucose tolerance need early management of the syndrome to prevent morbidity and mortality of diabetes and reducing the cardiovascular risk factor. In fact, the metabolic syndrome (insulin resistance syndrome) requires a much broader perspective than the focus on blood glucose levels alone^9,12,13,14.
In 1985 a new classification was introduced representing a compromise between clinical and etiological classification which included both staging of diabetes based on clinical descriptive criteria and a complementary etiological base^6,8,9,15.
A patient may acquire diabetes because of large doses of exogenous steroids and may appear normoglycemic, and once the gluco-corticoids are discontinued they may develop diabetes many years later⁹. Another example is gestational diabetes in which the patient may continue to be hyperglycemic even after delivery or may prove to be diabetic many years later.
For the clinician it is important to understand the pathogenesis of hyperglycemia to manage the case effectively. Many diabetic individuals do not fit easily into a single class. The etiological classification highlights the fact that diabetes can be identified even if the patient is normoglycemic^5,9.

Classification of Diabetes mellitus:
In 1997, the expert committee on the diagnosis and classification of diabetes mellitus published the following new classification:^16,17.

Type 1: Characterized by beta cell destruction leading to absolute insulin deficiency. It may present itself in two forms:
1. Autoimmune destruction of beta cells of the pancreas:
This form of diabetes accounts for 5-10% of cases previously described as IDDM or juvenile onset diabetes mellitus. The rate of beta-cell destruction is quite variable. Some cases present with ketoacidosis from the very beginning while others, especially the adults, may have only residual beta cell function, enough to prevent ketoacidosis for a long time but regarded as a high-risk group. Insulin is always required to prevent ketoacidosis, coma and death...
Autoimmune destruction of beta cell has multiple genetic predisposing factors and directly related to the surrounding environment^{3,8,9,18,19,20}.

2. Type 2: Characterized by predominant insulin resistance and relative insulin deficiency or vice versa.
This is the most common form of diabetes mellitus forming 90-95% of diabetic cases. It is highly associated with a family history of diabetes, older age, obesity and lack of exercise^15,21. It is more common in females especially those with a history of gestational diabetes, and in blacks, Hispanics and Native Americans.
The etiology of type 2 diabetes mellitus is usually multifactorial and probably genetically controlled, but it also has a strong behavioural component. Most patients are obese which causes some degree of insulin resistance. In the long run, those patients are also prone to macro and micro vascular complications^5,15,21.

Other specific types:

Impaired Fasting Glucose (IFG):
In these cases the fasting plasma glucose is higher than normal but lower than the diagnostic limits.

Impaired Glucose Tolerance (IGT):
The fasting plasma glucose is higher than normal and less than diagnostic following administration of glucose load of 75 grams. It is a stage of impaired glucose regulation rather than frank diabetes. Obesity with hyperglycemic disorder is a common manifestation in these cases.
IFG and IGT patients are considered as pre-diabetic and may be euglycemic in their daily life but are still at higher risk of cardiovascular diseases. However, the two lesions are different entities representing two abnormalities of glucose regulation in the fasting and the postprandial state^3,6,8,9,32.

Gestational Diabetes Mellitus (GDM):
This is a form of glucose intolerance in pregnancy with insulin resistance and beta- cell dysfunction. The lesion is usually diagnosed for the first time during pregnancy. Screening of these women in the first trimester is very useful^9,15,18,19.

Genetic defects of beta cell function:
Monogenetic defect in beta-cell function may present with hyperglycemia before the age of 25 years. It is an inherited disease of autosomal dominant pattern⁵.
The main insult is impaired insulin secretion without any defects in insulin action.

Genetic defects in insulin action:
These are rare cases resulting from abnormalities of insulin action. Some patients may have acanthosis nigricans. Some females may suffer from civilization or cystic ovaries^5,21.

Exocrine pancreas diseases:
Pancreatitis, cystic fibrosis, pancreatectomy, hemochromatosis or neoplasia; anyone of these conditions that diffusely affects the pancreas can cause diabetes.

Infections:
Many viruses have been associated with type 1 diabetes; HLA and immune markers have been detected in patients with congenital rubella. Coxsackie virus B, cytomegalovirus, adenovirus, and mumps are also linked to some diabetic cases¹⁵.

Endocrinopathies:
In conditions like acromegaly, Cushing's syndrome, glucagonoma, phaeochromocytoma, and hyperthyroidism, the hormones antagonize insulin action. Hyperglycemia resolves when the level of these hormones returns to normal¹⁵.

Drug or chemical induced:
Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, beta-adrenergic agonists, thiazides, phenytoin or Alfa-interferon may impair insulin secretion.

Uncommon immune diseases related to diabetes:
Stiff-man syndrome and systemic lupus erythematosus are examples of this category where anti-insulin receptor antibodies are detected.

Rare genetic syndromes associated with diabetes:
Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram syndrome, Friedreich's ataxia, Huntington's chorea, Lawrence-moon Beidel syndrome, myotonic dystrophy, porphyria, Prader-Willis syndrome^{3,5,8,9,18,19}.

Clinical manifestations and diagnostic criteria of diabetes mellitus:
Although most of the cases do not require sophisticated equipment for diagnosis of diabetes mellitus, the majority of cases are detected incidentally. The common symptoms of diabetes are frequent urination, polydypsia, unexplained weight loss, refraction errors, tiredness with the least effort, pruritis, slow healing sores, peripheral neuropathy including tingling and numbness sensation in the hands and feet^22,23.
Inadequate treatment and negligence may lead to the slow development of complications like Ketoacidosis, particularly in children.
In adults coma and nephropathy beginning with microalbuminuria and ending with renal failure, are a few examples of the devastation caused by this disease^{1,4,9,23,24,25}.
Risk factors of diabetes include ethnic groups; black, Hispanic, American Indian, pacific islander and overweight people with a Body Mass Index over 27 kg per m2, high blood pressure above 140/90 mm of Hg, high cholesterol, having first-degree relative with diabetes mellitus or previous history of gestational diabetes^3,8,26.

Laboratory investigations and clinical testing of diabetes mellitus:
The diagnostic criteria according to the laboratory investigations are changing from time to time, according to the collected epidemiological data. In 1985 WHO has settled a standard test based on 75-g oral glucose tolerance test^3,6,8,25.
WHO has also revised the previous threshold of fasting plasma glucose (FPG) and the 2-h plasma glucose (PG). The data collected showed that most of the patients having 2-h PG above the diagnostic threshold of 11.1 mmol/l have FPG less than the diagnostic threshold of 7.8 mmol/l while the patients with FPG above 7.8 mmol/l have 2h- PG above 11.1 mmol/l^3,6,8,15,25.
In 1997-1998 WHO and ADA suggested the definition of new intermediate stage of disturbed glucose metabolism named as IFG (Impaired fasting glycemia) and a new diagnostic threshold for this stage of 6.1-6.9 mmol/l. was suggested. Accordingly the normal FPG should be less than 6.1 mmol/l, while the 2h PG should be less than 7.8 mmol/l. For some populations at high risk of diabetes (e.g. Asian) FPG threshold is considered even lower than 6.0 mmol/l.
ADA suggested that FPG should be the diagnostic test of choice rather than the 2-h PG for clinical and epidemiological studies since it is simpler and more reproducible^5,9,15,18.
A glycated hemoglobin test also called glycosylated hemoglobin, glycohemoglobin or hemoglobin A1C was introduced as an important tool for diagnosis and follow up of diabetes.
Glycated hemoglobin as a screening test is easier for both patients and clinician because the blood sample can be drawn at the time of the patient's visit to the hospital^3,6.
These updates in diagnostic criteria and the lower cut-off for FPG will increase the number of diagnosed cases. 50% of cases according to the old criteria would remain undiagnosed for many years and those who are asymptomatic and undiagnosed would continue to develop diabetic complications^27,28.

Screening and recommendations:
The prevalence of diabetes worldwide affecting adults above 20 years was estimated to be 171 million in 2000 and expected to be 366 million in 2030^22,23. The number of people with diabetes is increasing due to population growth, increased life span, urbanization, and lack of physical activity. People above 65 years of age are the most affected lot.
Washington-based World watch institute reported that, for the first time in history, the number of overweight people in the world had outstripped those who are malnourished. Research findings indicate that the prevalence of diabetes will continue to rise even if the level of obesity remains constant.
The percentage of diabetics is much higher in Gulf countries, when compared to the other countries. The rapid change in this area after oil discovery and the marked increase in the family's income in the last three decades has affected the social and economic daily life. Sedentary life also has played an important role in this problem. Looking to the picture globally, it seems to be repeated all over the world; diabetes is prevailing in western countries faster than the developing countries. Modern civilization has produced major changes in the life style and eating habits.
When we come to obesity as one of the major causes of diabetes; the tables do not show a direct relationship between over weight and diabetes.

There is a big debate now about the mechanism that leads to the development of diabetes. It seems that many substances are involved with insulin in the process of homeostasis. Cannaboids, Neuropeptide Y, Ghrelin an Anandamid, along with glucocorticoids and leptin hormones can directly affect metabolism, energy consumption in the body and even appetite. The full mechanism that regulates insulin secretion, fat storage and energy balance still needs further studies^{10,14,18,44,45}.
Accurate numbers of people affected now and in the future by diabetes, is essential for rational planning. Out of sixteen million diabetic people in the U.S.A., 700,000 have type 1 diabetes and 15.3 million have type 2 diabetes¹⁸. Obesity and poor living conditions are mainly related to the prevalence of type 2 diabetes². Eight million did not know that they were diabetic.
In an effort to avoid these missing cases, new recommendations have been introduced by the international panel of experts, and have been endorsed by the national institutes of health. Testing for diabetes should be considered for all persons aged 45 years or higher^18,27. In the U.S.A. this group is about 77 million. The test should be repeated on another day for those who have shown a high reading and at three years intervals for people with normal results. Investigating this group may lead to the detection of two million new cases.
Groups at high risk of diabetes are;
- An obese person above 120% desirable body weight or body mass index (BMI) above 27 kg/m2.
- First degree relatives of known diabetics.
- People with low HDL < 35MG/dl and / or triglyceride level > 250 mg/dl.
- People who have a previous positive test of IGT or IFG.
The high risk individuals should be tested at a lower age and the test should be repeated more frequently^3,8.
Screening for gestational diabetes (GDM) should be done at 24-28 weeks especially for old, obese, hypertensive women with large babies weighing above 9 lb. About 4% of pregnant women in America develop diabetes during pregnancy resulting in 135,000 cases of diabetes annually. Deterioration of glucose tolerance occurs particularly in the third trimester^5,8.
Some ethnic groups with high risk factors should be tested periodically such as American Indians, Hispanics, Asians, and obese women⁵. Millions of diabetic cases could be diagnosed using these new criteria for screening and testing.
Early diagnosis of diabetes is the crucial factor to prevent eye, heart, kidney and neural damage since the risk of these complications increase sharply when FPG is above 6.1 mmol/l. The American Diabetes Association decided that the fasting plasma glucose test is sufficient for screening and could replace a more expensive, time consuming and unpleasant procedure, the oral glucose-tolerance test. The American Diabetes Association estimates that each year, complications of diabetes result in 54,000 amputations, 12,000 cases of blindness and 178,000 deaths from diabetes and its complications. However routinely reported statistics based on death certification underestimate mortality from diabetes because individuals with diabetes most often die of cardiovascular and renal diseases and not from a cause related specifically to diabetes such as ketoacidosis or hypoglycemia¹⁸.
Metabolic syndrome represents another challenging group in diagnosis and control. The features of the metabolic syndrome can be present for up to ten years before detection of hyperglycemia. This group is at high risk of macro vascular disease. This means that the management of persons with metabolic syndrome should include strategies for reduction of cardiovascular complications³².
Some recent studies claimed that there is no association between metabolic syndrome and the risk of cardiovascular diseases in elderly. They concluded that elimination of the aging factor with removing the risk imposed by smoking and high cholesterol along with uncontrolled blood pressure will disable any possibility of prediction of heart disease, In a prospective study of paravastatin in the elderly at risk the results showed that there is a four-fold increase in the risk of diabetes mellitus in people suffering from metabolic syndrome. They emphasized the importance of impaired blood glucose testing as a strong tool for prediction of diabetes since the same result showed more than an 18 fold increase in risk of incident diabetes³³.
Epidemiological studies confirm that this syndrome is common in wide ethnic groups including Caucasians, Mexican-American, Asian Indian, Chinese, Australian Aborigines, Polynesians and Micronesians. Central obesity, insulin resistance, hyperinsulinemia with one or more of the following components:
- Raised arterial blood sugar.
- Raised plasma triglycerides.
- Microalbuminuria.
- Hyperuricaemia.
- Coagulation disorders^9,28.
Testing presumably healthy individuals for the presence of any immune markers is not recommended as a routine, probably because accurate values for some assays for immune markers have not been completely established. There is also no agreement yet what action should be taken when a positive test is obtained. There are no definite measures that might prevent or delay the clinical onset of the disease. This type of autoantibody test is mainly useful to detect type1 diabetes only. The cost of such screening is very high since the incidence of type 1 diabetes is low^27,31.

General standards for diabetes management and self-management education:
Once diagnosis of any diabetic case has been made, an effective program for controlling blood sugar must be planned. Preventing diabetic complications is the main objective for any health care unit^2,6,18,22,31.
It is really unacceptable to detect a diabetic case for the first time having a heart attack or hemorrhage in the eye¹⁸.
Most diabetic cases of type 1 develop the disease in childhood or in adolescence, caused by severe deficiency in the hormones. These cases will require insulin therapy to control blood sugar together with some cases from other specific types of diabetes; in certain circumstances patients classified as type 2 diabetes may even need insulin therapy³². For people with type 2 diabetes blood sugar control should start by adjusting diet, encouraging physical exercise and modifying lifestyle. Patients with Type 2 diabetes are more likely to be over weight and hypertensive. Nutrition therapy and exercising may be enough to control some cases, especially the newly diagnosed cases but if these measures fail or the blood sugar is very high; oral medications may be needed^18,32.
The American Diabetes Association estimates that 10 to 20% of people with type 2 diabetes are treated with dieting and exercise, 30 to 40% with oral drugs and the rest with insulin and oral medications.
Diabetic complications can be prevented if the patient is taught how they can take care of themselves in leading an active, healthy life^31,32. This will depend on receiving good medical advice. Usually the general practitioner is responsible for daily advice in the primary health care centers but patients with risk factors will need thorough care from a specialist or even a team, comprised of professional diabetes educators. A caring support system is also required to deliver effective treatment, and to promote the necessary self-management skills to adapt behavioural changes. This will help to have optimum control on blood sugar. Many countries have established specialized diabetic centers to fulfill these objectives.
A successful dieting program may lead to decrease in caloric intake, reduced body weight, and healthy eating habits, to control blood sugar within normal range. Losing fat is far more important than losing weight³¹.
Hyperlipidemia may increase the risk of cardiovascular complications. Many studies showed that caloric control could reduce blood glucose level before any reduction of weight can be seen. Increased physical activity can also increase muscle bulk and improve tissue response to insulin without significant weight loss. Medical nutrition therapy and physical activity is more important for patients with type 2 diabetes^31,32.
Type 1 diabetes usually affects young children. According to the study published in the journal of the American Diabetic Association, daily carbohydrates and caloric intake may be less than required for young children with type1 diabetes because of rapid growth during the pre-school years.
The same study showed also that the children's daily intake of vitamin B-12 and calcium were below minimum dietary reference intake levels. Patients with type1 diabetes need a well-balanced, nutritionally adequate diet with insulin dose matched to carbohydrate intake, in order to control blood sugar³².
One of the major complications of type 1 diabetes is diabetic neuropathy. This problem can be treated by giving the patient subcutaneous injections of C-peptide doses. The result of the study proved that the treatment has improved both sensory and motor nerve conduction velocities. Vibration perception threshold has also improved³⁴.

Drug therapies:
Insulin presents the only choice for patients with type1 diabetes and is used to manage some cases of type2 where blood glucose levels cannot be controlled by diet, weight loss, exercise and oral medications. Using insulin as long-term therapy has many disadvantages. Subcutaneous injections of insulin drain in the peripheral circulation rather than the portal circulation. Its absorption is highly variable making the prediction of the glucose lowering effect very difficult. The different sites of injection have different absorption rates. Abdominal injections absorb faster than the thigh.
Human insulin which has been introduced lately, and is now widely available, is more soluble and more stable than the other forms previously used like bovine insulin. Reports of insulin resistance, allergy and atrophy of subcutaneous fat at the site of injection have decreased sharply after introducing human insulin. Weight gain and hypoglycemia are between the most common adverse reactions of insulin^18,32.
Oral hypoglycemic agents are used to treat type 2 diabetes. This group includes sulphonylureas, biguanides, alpha glucosidase inhibitors and thiazolidenediones. This group improves insulin resistance and stimulates insulin secretion⁴. Lately some papers have shown concern about the safety of the drugs used to treat type2 diabetes. Some drugs may contribute to heart diseases or increase the risk of them.
Rosiglitazone which was used for a long time to treat type 2 diabetes has been proved to be associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular diseases^18,35.
Anti-diabetic herbal agents have also been used a long time. A study by Atta-ar-Rahman has documented more than 300 plants species accepted for their hypoglycemic properties. Karela (corolla) also known as bitter gourd is a fruit cultivated in India, China, East Africa and South Africa; the studies proved that the fresh juices of this fruit could treat all symptoms of diabetes including polyurea, polydipsia, and polyphagia and can decrease urinary excretion of sugar³².
Diabetes Self-Management Education (DSME) is very important for any effective health-care related outcomes. Case studies and case report investigations about any successful management strategies confirm the needs of clear goals and objectives. Written commitments, policies, support, and the results will help quality improvement efforts. Reports, documentations and mission statement may help in promoting educational programs. Documentation from small as well as large health organizations provide a solid basis to deliver quality health services.
DSME should determine the target population, assess educational needs according to the ethnic background of the community and education level of the target group and identify the resources to tailor the appropriate program.
For any educational program to be effective, a professional staff comprises behaviorist, exercise physiologist, ophthalmologist, pharmacist, dietitian and registered nurse. There should be a system for continuous re-evaluation and planning after reviewing the process, including data analysis of the outcome measurements and forwarding the recommendations to a concerning governing board³¹.

International Comparisons of Diabetes costs
The economic burden of diabetes does not only affect the individual patients and their families but the state and health services on the whole. Study shows the costs of diabetes in 1992 in U.S. was $ 91.8 billion. The direct medical costs of diabetes, and its complications were $ 45.2 billion. Indirect costs were $46.6 billion. It is about 13% of U.S. healthcare expenditure³⁶.
The estimated direct medical costs of type 1 diabetes in England and Wales in 1992 were £95.6 million; indirect costs were £ 113 million³⁶. The cost of Diabetes in the U.S. was estimated at $ 132 billion in 2002 in medical expenditure and as a result of lost productivity³⁸.
Canadian healthcare systems estimated $ 13.2 billion expenditure on diabetes every year. They predicted that the costs will rise to $15.6 billion a year by 2010 and $19.2 billion a year by 2020^39,40.
In the year 2000-01 Australian diabetes costs burden was estimated at around $ 784 million.
Studies on the costs of diabetes have been conducted in France, Sweden, and Canada. These studies were not comprehensive as of the US. The French study shows that from the total medical expenditure of the selected subjects, the insulin-dependant patients direct cost was 5% and non-insulin- dependent was 8% which was spent on physician visits. In Sweden 14% was spent on physician visits only. Canadian studies showed a 20.9% spent as a direct cost of treatment³⁵.
The World Health Organization (WHO) estimated the cost of mortalities from diabetes, heart disease and stroke, about International Dollars (ID) 250 billion in the US, ID 225 billion in China and the Russian Federation and 210 billion ID in India in 2005.
In next 10 years WHO estimates that diabetes, heart disease and stroke together will cost about $555.7 billion in China, $303.2 billion in the Russian Federation, $333.6 billion in India, $49.2 billion in Brazil and $2.5 billion in Tanzania. It is expected that in 2007, the world will spend an estimated $215 billion to $375 billion for the care of diabetes and its complications. If nothing is done over the next 20 years, the figure will rise to $234 billion - $ 411 billion^41,43.
The estimated expenditure of the Eastern Mediterranean and Middle East Region (EMME Region) was between 2.8 and 5.2 billion International dollars (ID) in 2003. A less affluent country like Pakistan is estimated to spend between 430 and 800 million ID on Diabetes⁴³.
Saudi Arabia is estimated to spend between 620 and 1,142 million ID. According to WHO records, almost one Saudi diabetes mellitus person is costing the government about $800 per month. The annual cost of treating diabetes in Saudi Arabia is about $9.6 billion^38,42,44.

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