Weight loss, thiazolidinediones, metformin, sulfonylureas, insulin
large amounts, in proportion to the severity of disease and the intake of carbohydrates.
Fasting Blood Glucose and Insulin Levels. The fasting blood glucose level in the early morning is normally 80 to 90 mg/100 ml, and 110 mg/100 ml is considered to be the upper limit of normal. A fasting blood glucose level above this value often indicates diabetes mellitus or a least marked insulin resistance.
In type I diabetes, plasma insulin levels are very low or undetectable during fasting and even after a meal. In type II diabetes, plasma insulin concentration may be severalfold higher than normal and usually increases to a greater extent after ingestion of a standard glucose load during a glucose tolerance test (see the next paragraph).
Glucose Tolerance Test. As demonstrated by the bottom curve in Figure 78-12, called a "glucose tolerance curve," when a normal, fasting person ingests 1 gram of glucose per kilogram of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours.
In a person with diabetes, the fasting blood glucose concentration is almost always above 110 mg/100 ml and often above 140 mg/100 ml. Also, the glucose tolerance test is almost always abnormal. On ingestion of glucose, these people exhibit a much greater than normal rise in blood glucose level, as demonstrated by the upper curve in Figure 78-12, and the glucose level falls back to the control value only after 4 to 6 hours; furthermore, it fails to fall below the control level. The slow fall of this curve and its failure to fall below the control level demonstrate that either (1) the normal increase in insulin secretion after glucose ingestion does not occur or (2) there is decreased sensitivity to insulin. A diagnosis of diabetes mellitus can usually be established on the basis of such a curve, and type I and type II diabetes can be distinguished from each other by measurements of plasma insulin, with plasma insulin being low or undetectable in type I diabetes and increased in type II diabetes.
Glucose tolerance curve in a normal person and in a person with diabetes.
Acetone Breath. As pointed out in Chapter 68, small quantities of acetoacetic acid in the blood, which increase greatly in severe diabetes, are converted to acetone. This is volatile and vaporized into the expired air. Consequently, one can frequently make a diagnosis of type I diabetes mellitus simply by smelling acetone on the breath of a patient. Also, keto acids can be detected by chemical means in the urine, and their quantitation aids in determining the severity of the diabetes. In the early stages of type II diabetes, however, keto acids are usually not produced in excess amounts. However, when insulin resistance becomes very severe and there is greatly increased utilization of fats for energy, keto acids are then produced in persons with type II diabetes.
The theory of treatment of type I diabetes mellitus is to administer enough insulin so that the patient will have carbohydrate, fat, and protein metabolism that is as normal as possible. Insulin is available in several forms. "Regular" insulin has a duration of action that lasts from 3 to 8 hours, whereas other forms of insulin (precipitated with zinc or with various protein derivatives) are absorbed slowly from the injection site and therefore have effects that last as long as 10 to 48 hours. Ordinarily, a patient with severe type I diabetes is given a single dose of one of the longer-acting insulins each day to increase overall carbohydrate metabolism throughout the day. Then additional quantities of regular insulin are given during the day at those times when the blood glucose level tends to rise too high, such as at mealtimes. Thus, each patient is provided with an individualized pattern of treatment.
In persons with type II diabetes, dieting and exercise are usually recommended in an attempt to induce weight loss and to reverse the insulin resistance. If this fails, drugs may be administered to increase insulin sensitivity or to stimulate increased production of insulin by the pancreas. In many persons, however, exogenous insulin must be used to regulate blood glucose.
In the past, the insulin used for treatment was derived from animal pancreata. However, human insulin produced by the recombinant DNA process has become more widely used because some patients develop immunity and sensitization against animal insulin, thus limiting its effectiveness.
Relation of Treatment to Arteriosclerosis. Diabetic patients, mainly because of their high levels of circulating cholesterol and other lipids, develop atherosclerosis, arteriosclerosis, severe coronary heart disease, and multiple microcirculatory lesions far more easily than do normal people. Indeed, those who have poorly controlled diabetes throughout childhood are likely to die of heart disease in early adulthood.
In the early days of treating diabetes, the tendency was to severely reduce the carbohydrates in the diet so that the insulin requirements would be minimized. This procedure kept the blood glucose from increasing too high and attenuated loss of glucose in the urine, but it did not prevent many of the abnormalities of fat metabolism. Consequently, the current tendency is to allow the patient an almost normal carbohydrate diet and to give large enough insulin to metabolize the carbohydrates. This decreases the rate of fat metabolism and depresses the high level of blood cholesterol.
Because the complications of diabetes—such as atherosclerosis, greatly increased susceptibility to infection, diabetic retinopathy, cataracts, hypertension, and chronic renal disease—are closely associated with the level of blood lipids as well as the level of blood glucose, most physicians also use lipid-lowering drugs to help prevent these disturbances.
Although much rarer than diabetes, excessive insulin production occasionally occurs from an adenoma of an islet of Langerhans. About 10 to 15 per cent of these adenomas are malignant, and occasionally metastases from the islets of Langerhans spread throughout the body, causing tremendous production of insulin by both the primary and the metastatic cancers. Indeed, more than 1000 grams of glucose have had to be administered every 24 hours to prevent hypoglycemia in some of these patients.
Insulin Shock and Hypoglycemia. As already emphasized, the central nervous system normally derives essentially all its energy from glucose metabolism, and insulin is not necessary for this use of glucose. However, if high levels of insulin cause blood glucose to fall to low values, the metabolism of the central nervous system becomes depressed. Consequently, in patients with insulin-secreting tumors or in patients with diabetes who administer too much insulin to themselves, the syndrome called insulin shock may occur as follows.
As the blood glucose level falls into the range of 50 to 70 mg/100 ml, the central nervous system usually becomes quite excitable, because this degree of hypoglycemia sensitizes neuronal activity. Sometimes various forms of hallucinations result, but more often the patient simply experiences extreme nervousness, trembles all over, and breaks out in a sweat. As the blood glucose level falls to 20 to 50 mg/100 ml, clonic seizures and loss of consciousness are likely to occur. As the glucose level falls still lower, the seizures cease and only a state of coma remains. Indeed, at times it is difficult by simple clinical observation to distinguish between diabetic coma as a result of insulin-lack acido-sis and coma due to hypoglycemia caused by excess insulin. The acetone breath and the rapid, deep breathing of diabetic coma are not present in hypoglycemic coma.
Proper treatment for a patient who has hypoglycemic shock or coma is immediate intravenous administration of large quantities of glucose. This usually brings the patient out of shock within a minute or more. Also, the administration of glucagon (or, less effectively, epinephrine) can cause glycogenolysis in the liver and thereby increase the blood glucose level extremely rapidly. If treatment is not effected immediately, permanent damage to the neuronal cells of the central nervous system often occurs.
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