Conventional insulin therapy is characterized by a prescribed insulin formulation, dosage, and time of application. The quality of metabolic control is monitored by the diabetes care team. The patient performs blood glucose self-monitoring to prevent hypoglycemia but not as a basis for adapting treatment. Nutrition is inflexible, as the amount of carbohydrates and the time of eating are fixed in order to compensate for the blood glucose-lowering effect of insulin and physical work, and are mainly dictated by the pharmacokinetics of the injected insulin. Metabolic control in type 1 diabetes is poorer with conventional therapy than it is with intensified therapy [127]. For this reason, conventional therapy should be avoided in type 1 diabetes. For type 2 diabetes, it may be satisfactory.
By contrast, intensified (functional) insulin therapy is flexible. This aims to imitate physiological insulin secretion (but without combining insulin with C-peptide and amylin and without releasing insulin into the portal vein). The nutrition-independent (basal) insulin requirement is covered by an injection of long-acting insulin or several injections of intermediate-acting insulin or by continuous subcutaneous infusion at a basal insulin rate. In addition, bolus insulin is given to correct hyperglycemia or to cover nutrition-dependent insulin requirements. This method allows nutrition and physical activity to remain variable and also allows immediately correction of blood glucose deviations. However, it requires frequent self-monitoring of blood glucose and the diabetic subject must be able to adjust the insulin properly. The risk of weight gain is increased.
Practical Aspects
When type 1 diabetes mellitus is diagnosed, the patients need much attention, because they need to realize that they have acquired a life-long disease that will change their life. Usually the diagnosis is made because of deranged metabolism. These patients should initially be treated as inpatients. The ketoacidotic patient must be treated as an emergency case. The initial inpatient period should be used for intensive teaching and training which will be continued on an outpatient basis. To make insulin therapy easier, the use of insulin pens should be favored.
If insulin therapy is not initiated on a ward, it may for the purpose of training be started as conventional insulin therapy.
Conventional insulin therapy (CT) is usually performed with intermediate-acting human NPH insulin (NPH = neutral protamine Hagedorn) or mixtures of human NPH insulin and short-acting regular insulin (Table 1.20). Since the duration of action of NPH insulin is less than 24 hours it must be given twice a day or more often. Because there is a delay before NPH insulin begins to act, it is usually given 30-45 minutes before breakfast and dinner. In view of the nutrition-dependent insulin need over the course of the day, about two-thirds of the daily dose is given in the morning and one-third in the evening. If the postprandial blood glucose increment is unacceptably high, mixed insulins are given in the morning or also in the evening. The proportion of regular insulin in mixtures may be chosen anywhere in the range between 10% and 50%.
To compensate for the action of insulin, carbohydrate intake must be properly distributed over the day. The dietary regimen also depends on physical activity and must be developed by trial and error. As a proposal to start with, total daily carbohydrate intake may be divided in eight parts with two-eighths given at breakfast, one-eighth about 3-4 hours later, one-eighth at lunch, one-eighth in the afternoon, two-eighths at dinner, and one-eighth at bedtime. Unless there is an emergency, it is advisable to start insulin therapy with a low dose. The effect of this very first dose should be monitored by repeated blood glucose measurements. Thereafter, the insulin dose may be swiftly adjusted.
Given the appropriate social and educational background in the patient, type 1 diabetes should be treated with intensified insulin therapy (ICT) from the very beginning. At first, the diabetes care team will be responsible for the enterprise, while the patient is learning. After the teaching and training phase, the diabetic subject will take over responsibility step by step. According to the basis/bolus concept, basal insulin needs will be covered by two to three injections of NPH. The aim is to guarantee a permanent, fairly constant supply with insulin without causing hypoglycemia and to take into account the circadian variation of the insulin demand. Since the insulin demand usually begins to increase in the early morning at 3-4 A.M., the last dose of NPH is often given at bed time. The basal insulin dose is usually about 50% of the total daily insulin dose, or 0.7-1.0 U per hour. If it is difficult to find the right dosage, this can be tested over a 24-hour fasting period with close blood glucose monitoring. However, this procedure is rarely necessary.
The bolus injection should be used for correction of hyperglycemia. It should also be related to carbohydrate intake and should take account of the fact that in a circadian pattern the need for a carbohydrate unit is highest at breakfast time, being then about 1.3 times as high as in the afternoon and evening. The bolus is given subcutaneously either in the form of regular human insulin 15-30 minutes before the meal or in the form of the insulin analogues insulin lispro or insulin aspart at the beginning of the meal. If food intake is unpredictable, the injection of the fast-acting insulin analogues may be given immediately after the meal according to how much was actually eaten.
On average, 1.3-1.5 U insulin are needed to compensate for 10-12 g carbohydrates or for a hyperglycemia of 40-50 mg/dl. Vice versa, about 10-12 g carbohydrates are needed to elevate blood glucose by 40-50 mg/dl. Insulin therapy should always be accompanied by blood glucose monitoring, preferably self-monitoring by the diabetic subject (see Table 1.19).
In continuous subcutaneous insulin infusion (CSII), pump insulin is infused by means of a programmable precision insulin pump and infusion system. The action kinetics of pump insulin are similar to those of subcutaneously injected insulin. The amounts of basal and bolus insulin and the timing of the infusion are similar to those in ICT. CSII has the advantage that the action kinetics remain constant as long as the infusion site is not changed and that basal insulin infusion can exactly be adjusted to the circadian needs. The risk of hypoglycemia is usually lower than with ICT, but unnoticed pump errors with loss of insulin supply may result in rapidly developing ketoacidosis. Other technical problems can usually be easily solved without any danger to the patient.
For emergency treatment of ketoacidosis and other unusual situations, treatment handbooks should be consulted.
Various insulins and insulin analogues are available to meet the different pharmacokinetic requirements (Table 1.20). Insulin should be given strictly subcutaneously. Intracutaneous injection or injection into tendons and muscle sheaths will delay insulin action, while injection into the muscle will accelerate the action. The kinetics of insulin action also depend on the region into which insulin is injected-relatively fast in the abdominal region and slower in the arm or thigh. Even in the same region, the peak time of insulin action may vary considerably from day to day. The action of regular insulin starts much slower than physiological insulin secretion. For this reason, regular insulin should be given 15-30 minutes before meals. The duration of action is longer than the average duration of food digestion and absorption and usually requires a snack 3-4 hours after the injection in order to avoid hypoglycemia.
New insulins have been developed with the aim of improving the concept of physiological insulin substitution. Insulin glargine is a 30B-Arg-Arg insulin analogue with almost constant insulin kinetics over 24 hours [351]. The risk of hypoglycemia can be kept low. Insulin glargine seems to be useful as basal insulin in ICT and may be used for the evening dose in type 2 diabetes.
For meal-time insulin demand the bioavailability of regular subcutaneously injected human insulin