Clinical experience with U-500 regular insulin in obese, markedly insulin-resistant type 2 diabetic patients.

On a clinical basis, severe insulin resistance is defined as a situation in which a patient requires 200 units of insulin daily for 2 days (1). This definition was determined 50 years ago, when it was erroneously believed that the human pancreas secreted 200 units of insulin a day. Although it is now known that the normal pancreas secretes only 20–40 units of insulin a day, this clinical definition is helpful because it delineates a very small group of patients, many with a number of unusual underlying problems. In adults, the conditions associated with clinical insulin resistance are gross obesity, severe infection, Cushing’s syndrome, acromegaly, hemochromatosis, lipodystrophic diabetes, genetic insulin receptor abnormalities, insulin receptor antibodies, Werner’s syndrome (adult form of progeria), insulin degradation at the injection site, and high titers of IgG insulin binding antibodies (immune mediated). Gross obesity is by far the most common condition. Although a recent review (2) discussed the use of U-500 regular insulin in states of severe insulin resistance, no detailed description of how to start and adjust doses of this concentrated form of insulin was given. This article provides a treatment algorithm for the use of U-500 regular insulin and summarizes our experience with obese, markedly insulin-resistant type 2 diabetic patients. RESEARCH DESIGN AND METHODS — Nine patients with type 2 diabetes from our diabetes clinic (five women and four men [eight Latino and one African American], aged 49.4 10.0 years [mean SD], diabetes duration 13.0 7.6 years, BMI 40.0 5.1 kg/m) who received U-500 regular insulin for at least 6 months were prospectively studied. One patient left the program for a liver transplant at another hospital 5 months after U-500 insulin was started. Eight patients were tested for insulin binding antibodies, which were undetectable in six and detected in two at levels below those causing immune-mediated insulin resistance (1). The decision to switch to U-500 insulin therapy was the use of 200 units of insulin a day and HbA1c (A1C) levels of 8.5%, despite having been followed at least monthly by specially trained nurses for 6 months to adjust U-100 insulin doses. Five patients were also taking a maximal dose (2 g) of metformin. The initiation and dose adjustments of U-500 regular insulin are shown in Fig.1. The before-breakfast dose was adjusted based on the before-supper blood glucose level, and the before-supper dose was based on the fasting blood glucose value. Before-bedtime snacks were emphasized. Although Cochran et al. (2) suggested three injections a day if the total dose of U-500 insulin was 300–750 units (and four injections with a total dose of 750–2,000 units), we did not find that necessary. The range of our final dose was 150–625 units with four patients taking 300–625 units. Changes in weight and insulin dose were analyzed by the Wilcoxon’s signedrank test. Changes in A1C level were analyzed by a one-way repeated-measures ANOVA. Significance was accepted at P 0.05 (two-tailed test).