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 is too sluggish. Two insulin analogues avoid this problem: insulin lispro (28B-lysine-29B-proline human insulin) and insulin aspart (28B-aspartic acid human insulin). The action kinetics of these insulin analogues are fast enough to allow treatment without an interval between injection and meal and without a snack between main meals [352,353]. No benefit with regard to the risk of hypoglycemia could be established [354]. These analogues have also been used in CSH treatment [355].
Recently inhaled insulin was developed as a noninvasive alternative to subcutaneous insulin administration. From a proof-of-concept study in type 1 diabetic individuals [356] and an observation study in patients with type 2 diabetes [357] it was concluded that inhaled insulin may offer a practical, noninvasive alternative to insulin injections, because it maintains glycemic control without major side effects and may provide greater patient satisfaction than subcutaneously injected insulin. These first clinical studies will stimulate the development of this new form of insulin therapy [358,359].
The insulin analogues glargine, lispro, and aspart have only recently been introduced into clinical practice. Data on their long-term safety and benefit are not yet available and must be awaited before their advantages and disadvantages can be finally assessed. This may not be a theoretical argument, since the binding properties of the analogues to the insulin and IGF-I receptors are not always identical with those of human insulin [360–362]. However, postmarketing surveys of more than a million treatment-years have provided no evidence for any increase in mitogenic risk with lispro (T. Krause. personal communication, 2001).
While the DCCT [127] has clearly shown that intensified insulin therapy is superior to conventional insulin therapy, no long-term studies in type 1 diabetic subjects using combinations of insulin and oral drugs such as metformin or α-amylase inhibitors are available.
Pharmacological Treatment of Type 2 Diabetes
Glucose Metabolism
About 25% of newly diagnosed type 2 diabetic individuals can initially have their condition controlled by nonpharmacological treatment [125]. The others need additional pharmacological therapy. Metabolic control deteriorates continuously from the very start of the disease. For this reason, the number of subjects who need drugs will increase, and those who were initially on monotherapy will eventually need combination drug therapy [125].
Five classes of oral antidiabetic
