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According to the World Health Organisation diabetes mellitus is a state of chronic hyperglycaemia due to genetic and environmental factors. In type 1 diabetes mellitus there is no production of insulin whereas In type 2 diabetes mellitus there is insufficient insulin or cells do not respond to insulin present in the body (insulin resistance) (1). The most frequent form is type 2 diabetes that accounts for more than 85 % of cases , with type 1 diabetes accounting for 10% of cases ,specific and gestational diabetes with 5 % of cases (2).
According to WHO estimations more than 180 million people in the world have diabetes mellitus and this number will probably more than double by 2030 if no urgent action is taken. In 2005 it is estimated that up to 1.1 million people died from diabetes and 80 % of these deaths occurred in low and middle income countries such as Zimbabwe, half of these people being under the age of 70 and 55 % being women (2).
Diabetes mellitus was generally considered to be a rare condition in Africa before the 1990s. Evidence of increased incidence and prevalence of type 2 diabetes mellitus was provided by some epidermiological rapid in the history of the world and is characterized by a rise in the burden of researches carried out in that decade. (3). Africa is experiencing a demographic and epidemiological transition that is the most noncommunicable diseases.(4). Most reports published between 1959 and 1985 indicated a prevalence of diabetes below 1.4 percent with the exception of those those from South Africa where higher prevalence was seen.
In 1994 the prevalence of diabetes mellitus in Africa was 3 million(5). The highest prevalence being found in populations of Indian origin, followed by black populations and Caucasians. In South Africa and Tanzania, the prevalence of those of Indian origin was between 12 and 13 % (6). The prevalence in blacks in rural areas of Africa was generally below 1 percent and that of urban areas of Africa was between 1 and 6 percent. Prevalence of type 2 diabetes was low in both rural and urban communities of West Africa except in urban Ghana, where a high rate of 6.3 percent was recently reported (7). Moderate prevalence rates have been reported from South Africa with 4.8 percent in a semi-urban community in the Orange Free State, 6.0 percent in an urban community of the Orange Free State, 5.5 percent in Durban which is mostly occupied by the Zulu tribe, and 8 percent in Cape Town which is mostly occupied by the Xhosa tribe.
In Zimbabwe from 1991-97 the prevalence of diabetes mellitus increased from 150 to 550 per 100 000 people. According to the Zimbabwe National Health profiles (1996-98) the number of new cases recorded in the ages 15years and above rose from 2734 cases in1996 to 5114 in 1998 which is an increase of 87% of recorded cases.Diabetes mellitus is among the top five chronic conditions seen in Clinics in Zimbabwe. A survey carried out in 2005 recorded a prevalence of diabetes mellitus among the adult population of 10%.Many of these people were not aware of their increased glucose levels.
INSULIN AND ITS FUNCTION IN GLUCOSE METABOLISM
Chief among the functions of insulin is to maintain low blood glucose levels and counter the concerted action of some hyperglycemia-generating hormones .Disorders that go without treatment associated with insulin lead to severe hyperglycemia and shortened life span and this can be the case in untreated diabetes mellitus (1). Insulin is produced in the β-cells of the islets of Langerhans as a preprohormone. Removal of its signal peptide is done in the cisternae of the endoplasmic reticulum and it is packaged into secretory vesicles in the Golgi, after which it is folded to its native structure and then kept in this conformation by formation of 2 disulfide bonds (1,8). The center third of the molecule is cleaved by specific protease activity and it dissociates as C peptide.This leaves the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide.Plasma glucose levels regulate insulin secretion from the β-cells of the islets of langerhans.(8). Increased uptake of glucose by pancreatic β-cells results in a concomitant increase in metabolism which leads to an elevation in the ATP/ADP ratio. As a result there is inhibition of an ATP-sensitive potassium channel (KATP channel). The net result of this process is a depolarization of the cell leading to Ca2+ influx and insulin secretion (8).
(1,3) pecial transporter proteins found in cell membranes allow glucose that is in the blood to enter into a cell. These transporters are controlled indirectly by blood insulin in certain body cell types like muscle cells. Low levels of circulating insulin, or its complete absence, will prevent glucose from entering those cells as in typical type 1 diabetes. More commonly there is a decrease in the sensitivity of cells to insulin like the reduced insulin sensitivity that occurs in type 2 diabetes mellitus and resuls in a reduction of glucose absorption. In both instances there is cell starvation and weight loss that can be extreme. In other cases though not common, there is a defect in the release of insulin from the pancreas. The effect of this is the same and that is hyperglycaemia levels (1,8).
Activation of insulin receptors results in internal cellular mechanisms that affect glucose uptake by contolling the number and function of protein molecules found in the cell membrane that are responsible for glucose uptake into the cell. Myocytes and Adipocytes are the main body tissues that are mostly influenced by insulin in terms of being stimulated for glucose uptake. Myocytes are particularly important because of their critical role in movement, breathing and circulation and adipocytes are important because they store excess food energy against future needs. These two cell types form about sixty % of all cells in the human body (1,8).
Insulin binds to the extracellular portion of the alpha subunits of the insulin receptor. This causes a conformational change in the insulin receptor and there is activativation of the kinase domain situated on the intracellular portion of the beta subunits. This activated kinase domain autophosphorylates tyrosine residues on the C-terminus of the receptor as well as tyrosine residues in the IRS-1 protein. Consequently the following steps occur :
1. Phosphorylated IRS-1, in turn, binds to and activates phosphoinositol 3 kinase (PI3K).
2. PI3K catalyzes the reaction PIP2 + ATP → PIP3 + ADP.
3. PIP3 activates protein kinase B (PKB).
4. PKB phosphorylates glycogen synthase kinase (GSK) and thereby inactivates GSK.
5. GSK can no longer phosphorylate glycogen synthase (GS).
6. Unphosphorylated GS makes more glycogen.
PKB also facilitates vesicle fusion, resulting in an increase in GLUT4 transporters in the plasma membrane .After the signal has been produced, termination of signaling is needed and this can be by degradation and endocytosis of the receptor bound to insulin . In addition, signaling can be terminated by dephosphorylation of the tyrosine residues by tyrosine phosphatases. Serine/Threonine kinases are also known to reduce the activity of insulin. Finally, with insulin action being associated with the number of receptors on the plasma membrane, a decrease in the amount of receptors also leads to termination of insulin signaling (1,8,9).
Other functions of insulin outside glucose metabolism includes stimulation of lipogenesis, reduction of lipolysis and increase of amino acid transport into cells. Insulin is also involved in transcription, altering the cell content of numerous mRNAs. It also stimulates growth, DNA synthesis an effect it shares with insulin like growth factors and relaxin.(1,9).
DIAGNOSIS AND MONITORING OF DIABETES MELLITUS
Different tests can be used to diagnose and monitor blood glucose levels in diabetes mellitus patients and these include random and fasting blood glucose, oral glucose tolerance test, blood urea ,blood hydrogen, urinary protein, blood insulin, blood fructosamine and glycosylated haemoglobin (HbA1c) (1).
For diagnosis the OGTT , fasting and random blood glucose tests are ideal and according to the WHO guidelines, if the plasma glucose is less than 5.5 mmol/L then diabetes is highly unlikely. A fasting plasma glucose of 7.0 mmol/L or more, or a random glucose of 11.1 mmol/L or more makes diabetes likely possibility and the diagnosis is confirmed by a repeated abnormal test. If the fasting plasma glucose is between 5.5 and 6.9 mmol/L or between 5.5 and 11.0 mmol/L non-fasting an OGTT with 75 g anhydrous glucose should be done.(1)
Blood hydrogen,blood urea and urinary protein,can also be used in diagnosis of diabetes but only as non specific confirmatory tests for fasting,random blood glucose and OGTT.Blood Insulin is rarely measured in diagnosis of diabetes mellitus (1,8).
In the management and control of diabetes , blood glucose determined at the time of the clinic attendance can only give limited information and may not represent the overall closeness of control at other times therefore it has limitations in monitoring glucose control. The HbA1c test provides a better index of diabetic control than plasma glucose since it is not greatly affected by short-term fluctuations in plasma glucose (8).
GLYCOSYLATED HAEMOGLOBIN AND ITS IMPORTANCE
HbA1c is a form of haemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time (three to four months). In the normal 120 day lifespan of the red blood cell glucose molecules join to haemoglobin in a non enzymatic reaction forming HbA1c.In individuals with poorly controlled diabetes, increases in the quantities of the glycosylated haemoglobin have been noted (10,11). Once a haemoglobin molecule is glycosylated, it remains that way. A build up of HbA1c within the red blood cell reflects the average level of glucose to which the cell has been exposed during its life cycle(1,8).
Measuring HbA1c assesses the effectiveness of therapy by monitoring long term plasma glucose regulation. Monitoring of glycogenic status is considered a cornerstone of diabetes care and affects how physicians and patients adjust medical therapy as well as behavioural therapy (diet and exercise) (11,12). It has been shown in a randomised study that when health care providers and patients are informed about the HbA1c results blood glucose control is improved. Simply knowing the results improves glycemic control, either through improved efforts by the patient or by the provider (10).
GLUCOSE CONTROL IN DIABETICS
In a diet control study done among diabetics with HbA1c results available in the United States it was shown that , 39% had good control (HbA1c <7%) 36% had suboptimal control (HbA1c 7-9%) and 25% had poor control (HbA1c >9%) (13).
Public health laboratories in Zimbabwe do not offer the HbA1c assay for diabetic patients. Many patients are from poor socio-economic background and rely solely on public health facilities as they cannot afford private healthcare facilities. Thus, most Zimbabwean diabetics do not have any form of long term monitoring of their blood glucose levels and are at a risk of having high levels of HbA1c levels without them or their health care providers knowing it.
INCREASED HbA1c AND COMPLICATIONS OF DIABETES MELLITUS
A certain study showed that an average HbA1c level of 7.2% resulted in a 76% reduction in retinopathy , a 60% reduction in neuropathy , a 50% reduction in kidney disease and a 35% reduction in cardiovascular disease. (9,14). Another study in The united states Of America demonstrated unequivocally that maintainingclose to normal blood glucose levels significantly lowers a person's risk of developing complications of diabetes mellitus (9).
In a study done to determine the relationship of HbA1c levels to hospital admission of patients , it was found that the likelihood of admission increased with higher HbA1c levels. The number of admissions of diabetic patients with HbA1c levels in the range (10.8 % - 18.4 %) was higher with 5 481 admissions in a 3 year period compared with 2 566 admissions of patients with HbA1c levels in the reference region of 7.7 % - 8.1 %(11).