Most of the problems of insulin replacement in type 1 diabetes arise from the fact that subcutaneous injection or pump infusion remains is a non-physiologic route of administration. From the subcutaneous site of injection, insulin is absorbed into the systemic rather than the hepatic portal circulation. More importantly, as noted, there is considerable variability of absorption of subcutaneous insulin from one injection to another. Insulin analogues in large part overcome this problem.
As noted, there are now three rapid-acting insulin analogues: insulin lispro, insulin aspart, and insulin glulisine. All three have a rapid onset of action and peak as noted above, thereby improving 1- to 2-hour postprandial blood glucose control compared with regular insulin. These rapid-acting analogues must be used in conjunction with a basal insulin to improve overall glycemic control (figure 10). Importantly, the rapid-acting analogues have consistently outperformed regular insulin in having less late post-prandial hypoglycemia. This finding should not be surprising since the long duration of regular insulin is much longer than the gut absorption of a typical mixed meal.
Figure 10. Idealized insulin curves for prandial insulin with a rapid-acting analogue (insulin aspart, insulin lispro, or insulin glulisine) with basal insulin given as insulin glargine or insulin detemir. Each insulin preparation is responsible for either the prandial or basal component. Many patients find the basal insulins do not last the entire 24 hours and they give the insulin twice daily. B=breakfast; L=lunch; S=supper; HS=bedtime.
Regarding long acting insulin analogues, clinical trials have demonstrated lower fasting glucose levels and less nocturnal hypoglycemia with insulin glargine than with NPH insulin, advantages that are especially relevant in patients aiming for meticulous control (A1c <7%) or those with hypoglycemia unawareness. Trials with type 1 diabetes have shown similar results with insulin detemir, which, compared with NPH insulin, was equally effective in maintaining glycemic control. In general, hypoglycemia is reduced with both insulin analogues compared to NPH insulin. Since hypoglycemia is clearly one of the treatment-limiting aspects of type 1 diabetes therapy, the use of these analogues has gained wide-spread acceptance.
Patients with type 1 diabetes derive the greatest therapeutic benefit when basal and prandial analogues are used together, because the physiologic pharmacokinetics and pharmacodynamics of these analogues make separating the basal and prandial components of insulin replacement easier. As a general rule of thumb, half of the total daily dose of insulin is given as basal insulin, while the other half is given as prandial insulin. The amount of prandial insulin can initially be determined by approximating the percentage of calories consumed at each meal. As patients become more educated, however, they may alter the prandial dose by estimating the carbohydrate component of each meal or snack and taking a unit of insulin for a defined number of grams of carbohydrate (e.g., one unit for each 8, 10, or 12 grams of carbohydrate).