Objective: Evidence supporting the twice-daily administration of insulin glargine as an approach to address its waning effectiveness at the end of a 24 hour period is sparse. We hypothesized that insulin concentrations determined during the last four hours of a 24 hour period would be greater when identical doses of insulin glargine were administered twice-daily as compared to once-daily among type 1 diabetes patients. Research Methods: Ten subjects with insulin deficient type 1 diabetes were admitted for two 38-hour studies at least one week apart. Patients received full-dose insulin glargine once daily at 0800 and half-dose insulin glargine twice-daily at 0800 and 2000 for at least one week in random order prior to overnight studies. Overnight glucose was stabilized with intravenous insulin on the evening prior to study, and subjects fasted and did not receive short acting insulin during the study period. Insulin concentrations were assessed every 30 minutes with an ultrasensitive assay between study hours 20 and 24. Results: Insulin concentrations for the final four hours of study period did not differ between once-daily and twice-daily insulin glargine administration ( p = 0.38). Home glucose testing results and overnight plasma glucose concentrations did not differ between study conditions. Conclusions: These results demonstrate that insulin concentrations are equivalent during the last four hours of a 24-hour period when insulin glargine is administered once- or twice-daily. These findings do not support a role for twice-daily insulin glargine in the management of patients with type 1 diabetes.
The first long-acting insulin analog, insulin glargine, was introduced in the United States in 2001. It has since become a basal insulin of choice due to its once-daily dosing and its reduced peak activity, resulting in fewer episodes of hypoglycemia [1,2]. Nevertheless, it is a commonly held clinical notion that once-daily insulin glargine administration provides inadequate basal coverage for some patients with type 1 diabetes. Pharmacodynamic studies are consistent with the possibility that relative insulinopenia may occur with once-daily dosing. Lepore et al. showed that the “end of action” of insulin glargine was 22 ± 4 hrs in subjects with type 1 diabetes [
Ten subjects with type 1 diabetes mellitus (9 female) were studied on two separate occasions in a prospective, randomized, cross-over study. Inclusion criteria included age 18 - 50 years, diagnosis of type 1 diabetes at least one year prior to study enrollment, an A1c less than 9%, and basal-bolus therapy using insulin glargine. Exclusion criteria included complications requiring hospitalization within the last 12 months, allergy to insulin glargine, clinically significant chronic medical disease (AST greater than 2.5 timers upper limit of normal, creatinine greater than 1.8 mg/dl, hemoglobin less than 11 for males and less than 10 for females, or NYHA class III or IV heart disease), systolic and diastolic blood pressure above 180 or 110 mmHg, respectively, or active alcohol or drug abuse. The study was approved by the University of New Mexico Human Research Protections Office and all participants provided written informed consent.
After an initial screening visit to determine eligibility and to obtain informed consent, study subjects were randomized to receive insulin glargine as either one full-dose injection (0.2 units/kg) at 2000 hours or two half-dose injections (0.1 units/kg) at 0800 and 2000 hours. Subjects subsequently recorded fasting capillary blood glucose (CBG) levels prior to breakfast and in the evenings before dinner, and insulin glargine doses were titrated until fasting CBG’s were less than 150 mg/dl (8.33 mmol/l). Once the dose of study insulin remained unchanged for one week with fasting CBG’s less than 150 mg/dl (8.33 mmol/l), subjects were admitted for an overnight study.
Subjects were admitted to the University of New Mexico Inpatient Clinical Research Unit at 1500 on the afternoon prior to study. In order to avoid carryover of long-acting insulin from the previous day, subjects were instructed not to take any insulin glargine at home on the day of admission. All subjects received a 7 kcal/kg American Diabetic Association meal at 1800, and then fasted for the remainder of the study [
CBG concentrations were determined in duplicate using mixed venous blood with a standard, commercially available meter (Accucheck Advantage, Roach Diagnostics, Indianapolis, IN). Plasma glucose was assessed using the ACE Glucose Reagent (Alfa Wassermann, Caldwell, NJ). Free insulin concentrations were determined using an Ultra Sensitive Human Insulin Radioimmunoassay (Linco, St Charles, Missouri), which employs the double antibody/PEG technique to achieve a sensitivity of 0.2 mcU/ml when using a 100 microliter sample.
Validation of the use of the Linco ultra-sensitive human insulin radioimmunoassay for insulin glargine was performed using the methods of Owen et al. [
The primary outcome variable of the study was the serum insulin concentration during the final 4 hours of the 24-hour study period. It was determined that ten subjects would be adequate to provide 80% power to detect a 49 pmol/l difference in serum insulin during the last 4 hours of the 24-hour study period between the once-daily and twice-daily insulin glargine regimens using a paired student’s t-test with alpha equal to 0.05. Secondary outcome variables include all insulin and glucose concentrations over the 24-hour period and the results of home CBG testing during the week prior to admission. Results from the once-daily and twice-daily insulin dosing regimens were compared using ANOVA and the paired Student’s t test, when appropriate. Area under the curve (AUC) for insulin and glucose during the last four hours of study was calculated using the trapezoidal rule. Results are reported as mean ± SD, except in the figures, which depict mean ± SEM.
Subjects had a mean age of 40 ± 8 years, a mean duration of diabetes of 16 ± 10 years, and a mean BMI of 31 ± 8 m/kg2. All enrolled subjects were C-peptide negative (less than 1 pmol/ml) during hyperglycemia 60 minutes after ingestion of 8 ounces of Boost® nutritional beverage (Nestle HealthCare Nutrition, Inc., Minnetonka).