Timing of Insulin Before Meals Everyday
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      The inclusion of "Timing of premeal insulin administration (Timing)" in an Intensive Insulin
      Therapy regimen will reduce A1C by an average of 1% in type 1 diabetic patients who have
      initial A1C's between 7.0% and 9.0%.
    

Detailed description: 
      Data:

      The Rationale for Timing of the premeal insulin administration - In type 1 diabetes, very
      little, if any, endogenous insulin is available to handle the carbohydrate load which very
      rapidly enters the circulation after the start of a meal. In non diabetic individuals, a
      complex array of physiological events occurs prior to eating (often called the cephalic phase
      of insulin secretion) which prepares the pancreas for immediate release of preformed insulin
      when any meal related increase in blood glucose occurs. This rapid insulin secretion prepares
      the tissues (primarily muscle and liver) to take up glucose very rapidly and thereby prevent
      severe hyperglycemia in the postprandial state. Since significant absorption of all short
      acting insulins (e.g. insulin lispro, aspart, or glulisine) from the subcutaneous tissue does
      not occur for 15 minutes following injection (26), this delay often results in postprandial
      hyperglycemia. If the patient happens to be hypoglycemic prior to the meal, this delay can be
      advantageous, but if he/she is hyperglycemic, then severe postprandial hyperglycemia may
      result. A rationale solution to this problem would be to time the short acting insulin
      injection based on the premeal blood glucose, but aside from our one pilot study addressing
      this strategy, no clinical study has been published supporting this approach. Our grant
      application is designed to correct this deficiency and provide the scientific data to support
      this addition to intensive insulin therapy.

      We studied the effect of Timing a fixed dose of rapid acting insulin lispro (Humalog™) in
      twelve type 1 diabetic subjects who were all made hyperglycemic prior to a standardized
      diabetic meal (11). In all studies, the dose of insulin of 0.15U/kg (~10 units) remained
      constant and represented a typical dose utilized by type 1 diabetic patients prior to an
      evening meal. Each of the twelve diabetic volunteers participated in all four study arms (48
      total studies). The insulin lispro was given at the following times: 1) 30 minutes prior to
      meal time (-30 minutes), 2) 15 minutes prior to the meal time (-15 minutes), 3) at the meal
      (0 minutes), and 4) 15 minutes after the meal was begun (+15 minutes). As is shown in Figure
      1, a normal postprandial glucose excursion was observed when the insulin was taken 15 minutes
      prior to the meal. No postprandial excursion was observed when the insulin was taken 30
      minutes prior to the meal. This is the desirable outcome in a hyperglycemic individual. Of
      particular interest is the fact that when the insulin lispro was taken right at mealtime
      (which is the most common pattern in type 1 diabetic patients), significant postprandial
      hyperglycemia was observed. Figure 2 provides the integrated postprandial glucose excursion
      (above and below baseline) over the entire 5½ hour study and reflects the data in Figure 1.
      This study strongly supports the injection of insulin lispro at least 15 minutes prior to the
      meal when premeal hyperglycemia is present.

      To be certain that the absorption of insulin lispro was not different between the four
      studies which might account for the difference in postprandial glucose excursion; we measured
      free insulin levels during all four research studies. As is shown in Figure 3, when the
      insulin excursion concentrations are superimposed on each other for each study, no difference
      in insulin absorption occurred between the four insulin administration protocols. This data
      strongly supports the concept that timing of the insulin injection prior to the meal has a
      major effect on glucose kinetics following a meal. Utilization of Timing in an Intensive
      Insulin Therapy regimen should have a major beneficial effect of suppressing postprandial
      hyperglycemia and reducing A1C.

      Study Design:

      The proposed study will be a double-blind, randomized controlled trial of approximately eight
      months duration per patient. The volunteers will be screened and then randomized to either a
      Timing protocol (continuing with their Intensive Insulin Therapy regimen) or continuing their
      usual Intensive Insulin Therapy. All volunteers will utilize Continuous Glucose Monitoring
      every other month in order to provide data on the magnitude of postprandial hyperglycemia and
      the incidence of hypoglycemia.

      Insulin Timing Algorithm:

      Based on our preliminary data (24), we will utilize the following algorithm to time the
      premeal insulin administration dose: 1) premeal blood glucose >250 mg/dl = take insulin 30
      min before the meal, 2) premeal blood glucose between 250 and 150 mg/dl = take insulin 15
      minutes before the start of the meal, 3) premeal blood glucose between 150 and 75 mg/dl =
      take insulin at the start of the meal, and 4) premeal blood glucose < 75 = take insulin 15
      min after the start of the meal. Participants will remain on their current insulin to
      determine if the the timing algorithm is indeed effective. The advantages of this algorithm
      are that it is very easy to remember and practical for the typical patient with type 1
      diabetes. It is designed to keep the glucose between 100 mg/dl and 150 mg/dl. It will reduce
      the postprandial glucose excursion when most needed, i.e. when the premeal glucose is
      abnormally high and prevent hypoglycemia when the premeal glucose is low.

      Statistical Assessment

      Power Analysis:

      Our pilot data are the only data available in the literature that assesses the effect of
      timing of the pre-prandial short acting insulin dose. As detailed above, this pilot study was
      short term so did not include any assessment of changes in A1C. Since A1C is the primary
      endpoint in the proposed study, we had to estimate the change in A1C that would have occurred
      with the changes we observed in the integrated postprandial excursion (figure 1 above).
      Assuming that the postprandial glucose excursion is responsible for 50% of the A1C value
      (above the normal concentration of 5.5%) as has been estimated in type 1 diabetic patients
      (16,17), then the variance and mean change in integrated glucose excursion was used to
      estimate the change in A1C that would be expected in the proposed study. From this data, we
      calculated that an improvement of A1C of 1% (the difference in A1C between the control Arm A
      and the intervention Arm B would require 16 subjects per group to provide a power of 90% to
      detect this difference at a p<0.01. In order to control for a maximum drop out rate of 20%,
      we will recruit and randomize a total of 40 volunteers for each group (a total of 80
      subjects).

      Data Analysis:

      The primary endpoint for this study will be the difference in A1C levels between experimental
      Arm A (volunteers not utilizing Timing ) and Group B (volunteers utilizing Timing). This
      comparison will provide the net effect of Timing and the direct measure of the change in
      postprandial hyperglycemia. In addition, several sub analyses will be done. This comparison
      will control for any positive effects that Continuous Glucose Monitoring may have on A1C. In
      addition, we will integrate the area under the five hour postprandial glucose curve as
      provided each day by the Continuous Glucose Monitoring Data for the primary meal of the day
      (as stated by the patient - usually supper). This data will provide a mechanism of any
      improvement in A1C observed. Finally, as an indirect assessment of changes in postprandial
      hyperglycemia, changes in 1, 5-anhydroglucitol (Glycomark™) will be measured every month. We
      will utilize an "intention to treat analysis" to analyze the data obtained. Analysis of data
      will be done using NCSS computer software (42).

      Clinical Importance:

      If our pilot study is validated by the proposed randomized clinical trial in this grant
      application, a new parameter for control of postprandial glucose will become available for
      the patient with type 1 diabetes. To date, this concept has not been utilized by healthcare
      providers because no one has demonstrated that Timing will result in a reduction of A1C. Our
      proposed grant application is designed to obtain the data that will make the use of Timing an
      integral part of a glucose control algorithm. Our results are not restricted to type 1
      diabetic patients who utilize insulin lispro since all of the short acting insulin analogs
      exhibit approximately the same absorption insulin profile (26), Participants will remain on
      their current insulin regimen. If our hypothesis is proved correct, i.e., that the correct
      Timing of the premeal insulin bolus will reduce the A1C by an average of 1% in type 1
      diabetic individuals with A1Cs between 7.0% and 9.0%, then according to data generated by the
      Diabetes Control and Complications Trial, a significant reduction in the microvascular and
      macrovascular complications of diabetes will occur. In addition, the successful completion of
      this study will provide a stimulus to examine the Timing of premeal insulin in other groups
      of diabetic patients, including type 2 diabetic patients on insulin therapy, pregnant women
      with gestational diabetes, and children with type 1 diabetes. Finally, in this day and age of
      continuing increases in health care costs, the inclusion of Timing will not add any
      additional financial cost to the diabetic patient's intensive insulin therapy regimen.
    

Intervention name(s): Control; Study Arm B
Intervention type(s): Other; Other
Intervention description(s): Study Arm A will consist of patients with Type 1 diabetes who will continue their current intensive insulin therapy regimen with no additional interventions by the investigators. Their primary care providers will continue to manage their diabetes to obtain the best control as possible of their glucose, lipids, and blood pressure. Continuous Glucose Monitoring will be monitored. No timing of premeal insulin administration will be utilized in this arm.; Study Arm B will include participants with type 1 diabetes which will utilize "Timing" to adjust their pre-meal insulin dosages. Participants will continue taking their current insulin and will be placed on a continuous glucose monitor.
Other intervention name(s): Control group- No "timing" insulin administartion.; Intervention- "Timing" of insulin administration.
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: type 1 diabetes; continuous glucose monitoring; Intensive Insulin therapy