Diabetes mellitus a failure of regulation of blood glucose concentration

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Diabetes mellitus is an impaired ability to regulate the concentration of blood glucose as a result of a failure of the normal control by insulin. Therefore, the plasma glucose concentration is considerably higher than normal, especially after a meal. When it rises above the capacity of the kidney to reabsorb it from the glomerular filtrate (the renal threshold, 11 mmol/L), the result is glucosuria — excretion of glucose in the urine. As a result of glucosuria, there is increased excretion of urine because of osmotic diuresis; one of the common presenting signs of diabetes is frequent urination, accompanied by excessive thirst.

The diagnosis of diabetes mellitus is by measurement of plasma glucose after an oral dose of 1 g of glucose per kilogram body weight — an oral glucose tolerance test. Figure 10.14 shows the response of plasma glucose in a control subject; there is a modest increase, and then glucose is cleared rapidly as it is taken up into liver, muscle and adipose tissue for synthesis of glycogen and fatty acids (section 5.6). In a diabetic subject, fasting plasma glucose is higher than normal, and in response to the test dose it rises considerably higher (possibly to above the renal threshold) and remains elevated for a considerable time.

There are two main types of diabetes mellitus:

• Type I diabetes (insulin-dependent diabetes mellitus, IDDM) is due to a failure to secrete insulin as a result of damage to the P-cells of the pancreatic islets resulting from viral infection or autoimmune disease. There is also a genetic susceptibility; the concordance of IDDM in monozygotic (identical) twins is about 50%. IDDM

Figure 10.14 The oral glucose tolerance test in control and diabetic subjects.

commonly develops in childhood and is sometimes known as juvenile-onset diabetes. Injection of insulin and strict control of carbohydrate intake are essential for control of blood glucose. • Type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) is due to failure of responsiveness to insulin as a result of decreased sensitivity of insulin receptors (insulin resistance). There is a clear genetic susceptibility to type II diabetes, which usually develops in middle-age, with a gradual onset, and is sometimes known as maturity-onset diabetes.

Initially, insulin secretion in response to glucose is normal or higher than normal in people with insulin resistance, and they can maintain adequate glycaemic control, although they have an impaired response to a glucose tolerance test. When the demand for insulin exceeds to the capacity of the P-islet cells of the pancreas, overt diabetes is the result.

NIDDM is more common in obese people, and especially those with abdominal rather than subcutaneous obesity (section 6.2.3). Significant weight loss can often restore normal glycaemic control without the need for any other treatment. The so-called 'metabolic syndrome' (also known as syndrome X) is the simultaneous development of insulin resistance, hypertension and hypertriglyceridaemia, all associated with (abdominal) obesity.

As NIDDM develops, control of glucose metabolism can be achieved by using oral hypoglycaemic agents, which both stimulate increased insulin secretion and enhance insulin receptor function. Increasingly, as biosynthetic human insulin has become widely available, treatment of NIDDM includes insulin injection to maintain better control over blood glucose concentration.

Acutely, diabetics are liable to coma as a result of hypo- or hyperglycaemia:

  • Hypoglycaemic coma occurs if the plasma concentration of glucose falls below about 2 mmol/L, as a result of administration of insulin or oral hypoglycaemic agents without an adequate intake of carbohydrate. Strenuous exercise without additional food intake can also cause hypoglycaemia. In such cases oral or intravenous glucose is required.
  • Hyperglycaemic coma develops in people with insulin-dependent diabetes because, despite an abnormally high plasma concentration of glucose, tissues are unable to utilize it in the absence of insulin. The high plasma concentration of glucose leads to elevated plasma osmolarity, which results in coma. In such cases insulin injection is required.
  • Because glucose cannot be utilized, ketone bodies are synthesized in the liver (section 5.5.3). However, when the metabolism of glucose is impaired, there is little pyruvate available for synthesis of oxaloacetate to maintain citric acid cycle activity (section 5.4.4). The result is ketoacidosis together with a very high plasma concentration of glucose. In such cases insulin injection is required, as well as intravenous bicarbonate if the acidosis is severe.

In the long term, failure of glycaemic control and a persistently high plasma glucose concentration results in damage to capillary blood vessels (especially in the retina, leading to a risk of blindness), kidneys and peripheral nerves (leading to loss of sensation) and the development of cataracts in the lens of the eye and abnormal metabolism of plasma lipoproteins (which increases the risks of atherosclerosis and ischaemic heart disease). Two mechanisms have been proposed to explain these effects:

  • At high concentrations, glucose can be reduced to sorbitol by aldose reductase. In tissues such as the lens of the eye and nerves, which cannot metabolize sorbitol, it accumulates, causing osmotic damage.
  • As shown in Figure 10.15, glucose can react non-enzymically with free amino groups on proteins, resulting in glycation of the proteins. Glycated proteins include:
  • Collagen. This may explain the problems of arthritis experienced by many diabetic subjects, as well as the thickening of basement membranes that is associated with blood capillary and kidney damage. Diabetic retinopathy, a cause of blindness, is the result of capillary damage in the retina.
  • Apolipoprotein B. This may explain the increased risk of atherosclerosis and ischaemic heart disease associated with diabetes and poor glycaemic control.
  • a-Crystallin in the lens. This may explain the high prevalence of cataracts associated with diabetes and poor glycaemic control.
  • Haemoglobin A. Glycation of haemoglobin A (with the formation of what can be measured as haemoglobin A ) provides a sensitive means of assessing the adequacy of glycaemic control over the preceding 4—6 weeks. It provides a better index of compliance with dietary restriction than a simple spot test of plasma glucose.
Figure 10.15 Non-enzymic glycation of proteins by high concentrations of glucose in poorly controlled diabetes mellitus.

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