Diabetes mellitus

Synonyms :  Diabetes; Hyperglycaemia; Hyperglycemia

Clinical features, Diagnosis, Management, Prognosis, Nutrition, Herbs,

Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia due to absolute or relative deficiency of insulin, which affects the metabolism of carbohydrate, proteins and fat. Diabetes has been crudely and conveniently classified in two main types:

       insulin-dependent diabetes mellitus (IDDM; also known as juvenile onset or Type I diabetes), which accounts for 10% of all diabetic cases

       non-insulin-dependent diabetes mellitus (NIDDM; also known as maturity onset or Type II diabetes) which is responsible for the remaining 90% of cases 

Although the precise aetiology is still uncertain in both main types of diabetes environmental factors interact with a genetic susceptibility to determine which of those with the genetic predisposition will actually develop the clinical syndrome. 

1. IDDM

         Basically IDDM is a slow autoimmune disease against pancreatic islet insulin secreting cells, which could be triggered by certain environmental factors (an early infection with Echo or Coxsackie viruses is suggested, as well as early exposure to cow protein in milk).

         The inheritance is polygenic (more than one gene appear to be involved) with strong association with a tissue antigenic marker HLA DR4. Many presumed autoimmune disorders are associated with specific HLA markers (e.g., ankylosing spondylitis with B27, multiple sclerosis DR2 etc.) although the exact pathophysiologic basis of this association in unknown.

         Hyperglycaemia accompanied by the classical symptoms of diabetes occurs only when 90% of insulin-secreting cells are already destroyed.

         Circulating b-cell and insulin autoantibodies can be identified, and also lymphocyte infiltration of pancreatic islets resulting in selective destruction of insulin-secreting cells can be demonstrated.

         Peak onset is at age 11 to 13, it is rare in adults over 30 years of age. 

2. NIDDM

         NIDDM is not HLA linked and there is no evidence that autoimmunity or viruses have anything to do with its development.

         It seems that genetic factors are more important in the development of this type of diabetes than in IDDM (it is now thought that susceptibility is inherited through an autosomal recessive trait).

         Epidemiological studies provide evidence that over-eating, especially when combined with obesity and underactivity, is associated with the development of NIDDM. Obesity probably acts as a diabetogenic factor through increasing resistance to the action of insulin in those genetically predisposed (80% of Type II diabetics are obese). This resistance is reversible and weight loss can restore sensitivity to insulin in most cases.

         Insulin resistance is probably due to a decreased number of cellular insulin receptors in peripheral tissues, maybe even associated with a post-receptor defect in the action of insulin.

         Also ageing is an important risk factor for NIDDM; the condition starts to increase after age of 40; but younger people may be affected (so called MODY ? maturity onset in young) 

Insulin has several essential metabolic actions as a fuel-storage hormone, and also affects cell growth and differentiation. It decreases blood glucose by: increasing glucose uptake, increasing glycogen synthesis, decreasing gluconeogenesis and decreasing glycogen breakdown 

Insulin increases fatty acid synthesis and triglyceride formation in the liver and adipose tissue (lipogenesis) and decreases lipolysis. Insulin stimulates the uptake of amino acids into muscle and increases protein synthesis. It also decreases protein catabolism and the oxidation of amino acids, particularly in the liver. 

Whatever the aetiology, in all cases the hyperglycaemia of diabetes develops because of an absolute (IDDM) or relative (NIDDM) deficiency of insulin which leads to:

       a reduced rate of removal of glucose from the blood by peripheral tissues

       an increased rate of release of glucose from the liver into the circulation due to action of counter-regulatory hormones (adrenaline and glucocorticosteroids), which is a compensatory mechanism; however this mechanism manages only to further increase the blood glucose levels. 

When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine (glycosuria) and causes an osmotic diuresis (polyuria) which in turn results in thirst and increased fluid intake (polydipsia). Patients also consume more food to compensate for lost glucose (polyphagia). Muscle wasting occurs in severe diabetes due to the fact that protein metabolism is deranged and an excessive amount of protein is converted to glucose (gluconeogenesis). 

In the absence of insulin and consequently impaired carbohydrate metabolism, energy can only be sourced from lipid breakdown (lipolysis) and b-oxidation of fatty acids. Unfortunately not all tissues are capable of b-oxidation but they (including the brain) can use partially metabolised fatty acids called ketone bodies (aceto-acetic acid, b-hydroxybutyric acid and acetone) formed from fatty acids in the liver (ketogenesis). When the rate of production exceeds that of removal by peripheral tissues (which is relatively slow in the absence of glucose metabolism), then hyperketonaemia results. Aceto-acetic and b-hydroxybutyric acids are relatively strong acids that cause a fall in pH (ketoacidosis) and stimulate pulmonary ventilation so that clinically hyperpnoea or ‘air hunger?is observed (respiratory compensation of metabolic acidosis). 

When insulin deficiency is partial, as in NIDDM, the anticatabolic effect of insulin (anti-lipolytic and anti-proteolytic) may be relatively well preserved while other metabolic actions are more seriously defective. In these circumstances lipolysis is not markedly accelerated and the concentration of ketone bodies in the blood remains relatively normal despite severe hyperglycaemia. In its most serious form this condition is known as hyperosmolar diabetic coma.

Clinical features:  < BACK TO TOP >

Feature	IDDM	NIDDM
Age of onset	< 20 years	> 50 years
Duration of symptoms before diagnosis	Days-weeks	Months-years
Body weight	Normal or low	Obese
Ketonuria	Yes	No
Autoantibodies	Yes	No
Diabetic complications at diagnosis	No	10-20%
Family history of diabetes	No	Yes
Other autoimmune diseases	Yes	No
Rapid death without treatment with insulin	More likely	Less likely

 

Patients with IDDM usually show no physical signs attributable to diabetes, but instead present with salt and water depletion (loose dry skin which lifts in folds, a dry furred tongue and cracked lips, tachycardia, hypotension and reduced intraocular pressure noticed as soft eyeballs on palpation). Breathing may be deep and sighing due to acidosis, the breath is usually fetid and the fruity-sweet smell of acetone may be apparent (acetone is the only volatile ketone body). Mental apathy, confusion or coma may also be present due to brain dehydration and reduced energy production.  

The physical signs present in patients with NIDDM at diagnosis are variable. In many instances NIDDM is discovered in asymptomatic patients during routine testing of urine/blood. Other may complain of polyuria, polydipsia and polyphagia, as well as vaginal thrush and balanitis (inflammation of the penis glans) since the external genitalia are especially prone to infection by fungi (Candida) which flourish on skin and mucous membranes soaked in glucose. Bacterial skin infections such as boils are also common. Impairment of vision may be reported when ophthalmoscopy may show the typical appearances of diabetic retinopathy, which are virtually diagnostic of the condition. Depression or loss of the tendon reflexes at the ankles and impaired sensory perception distally in the legs indicate neuropathy. The presence of diabetic nephropathy may be indicated initially by proteinuria in addition to glycosuria.  

Diagnosis:  < BACK TO TOP >

The earlier diabetes is diagnosed the easier it is to treat effectively and greater the chance of avoiding the development of serious vascular disease. When the symptoms suggest diabetes the diagnosis may be confirmed by finding glycosuria (glucose in urine), with or without ketonuria (ketone bodies in urine), and a plasma (serum) glucose concentration greater than 7.7 mmol/L (normally up to 6 mmol/L) after an overnight fast. 

Testing the urine for glucose by using reagent strips is the most usual screening procedure for detecting diabetes, but not completely reliable due to individual variations in renal threshold (false positive and false negative results in terms of diabetes diagnosis are possible). Ketonuria si common in IDDM but usually not in NIDDM. However, ketonuria may be found in healthy people, e.g., who have been fasting or on very strict diet poor in carbohydrates, and therefore it is not pathognomonic of diabetes. However if both ketonuria and glycosuria are found, the diagnosis of diabetes is practically certain. All patients with glycosuria should be considered diabetic until proved otherwise on the basis of blood measurements. 

Glucose tolerance test is done when plasma glucose concentration is between 6 and 7.7 mmol/L. A sample of blood is taken to measure the fasting plasma glucose level and 75 g glucose is dissolved in 300 mL of water and given by mouth. Thereafter samples of blood are collected at half-hourly intervals for at least two hours and their glucose content is measured. The patient is diabetic if plasma glucose 2 hours after glucose drink is >11 mmol/L (normally is less than 7.8 mmol/L). Intermediate readings are classified as Impaired Glucose Tolerance and it may be necessary to keep the patient under observation and to repeat the test at a later date. However in many patients with impaired glucose tolerance test the condition does not progress or it resolves spontaneously.

Management  < BACK TO TOP >

Three methods of treatment are available:

?diet alone
?diet and oral hypoglycaemic drug
?diet and insulin

Approximately 50% of new cases of diabetes can be controlled adequately by diet alone, 20-30% will need an oral hypoglycaemic drug, and 20-30% will require insulin.  

1. Dietary management. Dietary measures are required in the treatment of all diabetic patients to achieve the overall therapeutic goal: normal metabolism. Two basic types of diet are used:

       Low energy, weight reducing diet for obese diabetics

       Weight maintenance diet, which purpose is to keep the intake of food constant in content and pattern of distribution from day to day

It is important to realise, and to explain to the individual patient, that the ‘diabetic diet?/i> is simply that which is now recommended for the population in general, which includes intake of complex carbohydrates and avoidance of too much refined sugar, small meals more frequently instead of infrequent large meals.  

2. Oral hypoglycaemic drugs rely in their action upon a supply of endogenous insulin and they therefore have no hypoglycaemic effect in patients with IDDM.

         Sulphonylureas (e.g., chlorpropamide [Diabinese], tolbutamide [Rastinon], glibenclamide [Daonil, Semi-Daonil, Euglucon, Glimel], glipizide [Minidiab, Melizide], gliclazide [Diamicron], troglitazone [Rezulin] and glimepiride [Amaryl]) act by stimulating the release of insulin from the pancreatic beta cells, and are valuable in the treatment of non-obese patients with NIDDM, who fail to respond to dietary measures alone (sulphonylureas increase appetite that may result in weight gain and increased resistance to insulin).

         Metformin [Diaformin, Glucophage, Glucohexal, Diabex] increases insulin sensitivity and peripheral glucose uptake, without increasing insulin secretion, and may be a better option for obese patients with NIDDM.  

3. Insulin. The main types of insulin preparations are used clinically:

       unmodified, soluble with rapid onset and short duration of action (6-8 hours) such as Actrapid, Humulin R and Hypurin Neutral.

         intermediate-acting depot preparations such isophane insulin where insulin is adsorbed on to a foreign protein, normally fish protamine [Protaphane, Humulin NPH, Hypurin Isophane, Isotard MC] have duration of action of 12-24 hours. They can be mixed with soluble insulin and they are given subcutaneously.

         long acting, e.g., insulin zinc suspension [Monotard, Humulin L, Lente MC, Ultratard, Humulin UL] has duration of action of 24-36 hours. This suspension contains excess free zinc and when mixed with unmodified insulin the zinc will blunt the onset of its actions. This is why they should not be mixed together. Insulin zinc can be administered only subcutaneously.  

Insulin can be extracted from porcine or bovine pancreas. ‘Human? insulin is made by micro-organisms, usually E coli, modified through recombinant DNA technology and today is most commonly used. It is usually given subcutaneously, sometimes in an emergency room by intravenous infusion. 

Various regimes of insulin administration may be used. A common regime for IDDM patients is to inject a combination of short and intermediate-acting insulins twice daily, before breakfast and before the evening meal. These pre-mixed preparations are marketed as Mixtard 50/50, Mixtard 30/70, Mixtard 15/85, Humulin 50/50, Humulin 30/70, Humulin 20/80. Intravenous infusion of soluble insulin is used routinely in emergency treatment of diabetic ketoacidosis, in conjunction with large volumes of isotonic saline and potassium chloride to rectify Na⁺, K⁺ and Cl^- depletion.  

4. New developments are insulin that is administered into the nose through a spray (no need for injection) and drugs that mimic the action of insulin by activating insulin receptors but are given orally. They are still in research phase.

Acute Complications Of Treatment 

         Hypoglycaemia may occur due to over-dosage with insulin, missed meal or unaccustomed too strenuous exercise. Symptoms: weakness, emptiness, hunger, diplopia (seeing in duplicate), blurring of vision, mental confusion, abnormal behaviour (e.g., aggression, poor co-ordination), lassitude, somnolence, muscular twitching, nausea, vomiting, coma.

         Diabetic ketoacidosis in established diabetics develops if patients for some reason reduce their dose of insulin, or sustain a stress particularly that produced by intercurrent infection. Hyperglycaemia is combined with acidosis due to accumulation of ketone bodies, as well as severe dehydration and intracellular potassium depletion because of redistribution of potassium from intracellular to extracellular compartments in exchange for hydrogen ions. If potassium is not replenished, serious cardiac arrhythmias can occur.   

	Hypoglycaemia	Ketoacidosis
Cause	No food, too much insulin, unaccustomed exercise	Too little or no insulin, an infection
Onset	In good previous health, related to last insulin injection	Ill health for several days
Symptoms and signs	Hypoglycaemia Hunger, weakness, occasionally nausea and vomiting Moist skin and tongue Full pulse, moderate tachycardia Normal or raised blood pressure Shallow or normal breathing Normal reflexes	Glycosuria, polyuria and dehydration Abdominal pain and vomiting Dry skin and tongue Weak and rapid pulse Low blood pressure Air hunger (hyperpnoea) Diminished reflexes
Urine	No ketonuria No glycosuria	Ketonuria Glycosuria
Blood	Hypoglycaemia Normal plasma bicarbonate	Hyperglycaemia Reduced plasma bicarbonate

Diabetic ketoacidosis is a medical emergency which should be treated in hospital by:

       the administration of unmodified insulin by intramuscular or intravenous injection

       fluid and potassium replacement

       the administration of antibiotics if infection is present  

Long Term Complications Of Diabetes 

Large blood-vessel disease accounts for about 70% of all deaths. Atherosclerosis occurs commonly and extensively in diabetic patients with pathological changes similar to those seen in non-diabetics but occurring earlier and being more widespread, causing ischaemic heart disease, cardiac failure, intermittent claudication (crampy pain in calves on walking due to ischaemia), gangrene and stroke. Myocardial infarction is the most common cause of death in diabetics.  

Disease of small blood vessels in form of widespread thickening of their walls is specific to diabetes and is termed diabetic microangiopathy. It contributes to the mortality, particularly in younger people, by causing chronic renal failure (second most common cause of death) due to diabetic nephropathy (it takes at least 15 years). Diabetic retinopathy can cause severely impaired vision and blindness (it is now the commonest cause of blindness in the 35-65 age group in most developed countries). Diabetic neuropathy (affecting motor, sensory and autonomic nerves) can cause difficulty in walking, chronic ulceration of the feet, bowel and bladder dysfunction (constipation and urine retention), erectile dysfunction in men, diminished sensory perception, paraesthesiae (tingling), pain in the lower limbs, burning sensations in the soles of the feet.  

The incidence of the diabetic complications is mainly related to duration of diabetes and the degree of metabolic control achieved indicated by the mean blood glucose concentration. In most centres periodical determination of glycosylated haemoglobin (Hb A_1c) is done to estimate plasma glucose in the last 1-3 months. Hb A_1c is a stable product of non-enzymatic glycosylation of the b–chain of Hb by plasma glucose and hyperglycaemia as in diabetes generally increases the rate of formation of this type of Hb. Normal Hb A_1c level is about 6%, and in poorly controlled diabetics it is 9-12%. Similar test is fructosamine level which measures the level of fructosamine which is formed by a chemical reaction of glucose with plasma protein. Fructosamine reflects glucose control in the previous 1-3 weeks.  

It seems that all complications are irreversible and an effort must be put to prevent their occurrence by better control of diabetes, with full participation of patients.