Comparison of Carbohydrate Counting and Food Insulin Index Methods in the Determination of Insulin Doses for High- and Low-Glycemic Index Meals in Adolescents With Type 1 Diabetes
Phase: NA
Conditions: Insulin-Dependent Diabetes Mellitus 1
Sponsor: TC Erciyes University

Official Title of the study: Comparison of 
Carbohydrate Counting and Food Insulin Index 
Methods in the Determination of Insulin Doses for 
High-and 
Low-Glycemic 
Index 
Meals 
in 
Adolescents with Type 1 Diabetes
NCT number:
Document Date: 21 November 2018 (The date on 
which the uploaded document was approved by a 
human subjects protection review board.)

1. Background
Type 1 diabetes is an autoimmune disease characterized by chronic hyperglycemia resulting 
from an absolute endogenous insulin deficiency. In type 1 diabetes management, premeal 
insulin dosage and physiological insulin requireme0nt must be matched to maintain optimal 
blood glucose control (1). Intensive insulin therapy is the preferred treatment for individuals 
with type 1 diabetes. It can be an effective way of controlling blood glucose levels and 
minimising the risk of long term diabetic complications (2, 3). Insulin delivery is achieved 
subcutaneously using multiple daily injections or subcutaneous insulin infusion using insulin 
pumps. It provides the calculation of insulin doses according to the carbohydrate content of the 
meal and pre-meal blood glucose levels. It can also provide a less restricted lifestyle to 
individuals with type 1 diabetes by providing flexibility in meal time, quantity and frequency 
(4, 5).
Achieving glycemic control is important for patients with diabetes because it effects the 
development of diabetic complications. Diabetes control is mainly assessed according to 
HbA1c, fasting blood glucose and blood glucose measured two hours after meal consumption. 
In the control of type 1 diabetes, not only regular use of insulin is sufficient, but also important 
in balanced diet and regular physical activity. An individualized diet plan in particular is the 
corner-stone to proper metabolic control (6).
Currently, there are algorithms based on the carbohydrate content of the meal to calculate the 
meal insulin dose in patients with type 1 diabetes receiving intensive insulin therapy. One of 
these algorithms, the carbohydrate counting method (CC), is considered the “gold standard” for 
estimation of meal-time insulin dose. CC assumes that only carbohydrates influence the dose 
of insulin required and that equal portions of carbohydrate produce a similar glycemic response 
and require the same amount of exogenous insulin to be metabolized (7, 8). However, the effects 
of carbohydrates in food on increasing blood glucose levels are not equal and this concept is 
defined as glycemic index (GI). Studies have shown that GI is also a parameter affecting blood 
glucose level (9). The GI value of the food together with the CC provides the most accurate 
estimation of the insulin response in determining the meal insulin dose (7, 8, 10). Despite the 
use of insulin therapy and CC in individual with type 1 diabetes, many individuals continue to 
experience unanticipated hyperglycaemic and hypoglycaemic events that increase the risk for 
development of complications and reduce quality of life. These complications occur especially 
after a high-protein or high-fat meal is consumed. Although carbohydrate is the predominant 
macronutrient affecting postprandial blood glucose level, recent research has shown that dietary 
fat and protein can significantly affect the postprandial glucose excursions and thus adjusting 
the prandial insulin dose for these macronutrients may be beneficial (10-13).
Food Insulin Index method (FII), which is another method used to determine meal insulin dose, 
has been proposed which ranks foods based on the insulin response in healthy subjects relative 
to an isoenergetic reference food (either glucose or white bread) (14). The algorithm uses food 
energy as the constant, and thus all dietary components and their metabolic interactions can be 
considered for any food with sufficient energy density, allowing a holistic approach to 
determining insulin demand. It has shown that FII is more advantageous than CC in the control 
of postprandial blood glucose levels in people with type 1 diabetes especially after high fat and

protein meal (1, 8, 12, 13, 15). In addition, it was found that there was a correlation between 
meal insulin dose calculated according to FII and observed insulin response (1).
In summary, it is important to maintain blood glucose levels within the normal range in 
individuals with type 1 diabetes. In order to achieve this, the insulin demands of the foods 
consumed in the meal must be estimated accurately. Today, CC method is used in the 
calculation of meal insulin dose. GI is also known to affect blood glucose levels. Knowing the 
GI of foods together with CC provides the most accurate estimate of insulin response. However, 
the CC is insufficient to calculate the insulin dose, especially for high-fat or high-protein meals. 
It has been shown that the newly developed FII method which determines insulin demand by 
using energy of nutrients is advantageous compared to carbohydrate counting method in 
keeping blood glucose levels within normal range. However, studies have not evaluated the 
effect of GI on blood glucose levels when comparing CC and FII method.
2. Objective
The aim of this study is to compare the impact of carbohydrate counting (CC) method which is 
standard insulin dose calculation algorithm and food insulin index (FII) method which is a new 
algorithm on postprandial glucose following high fat and high protein meals with different GIs 
in adolescent with type 1 diabetes.
3. Materials and methods
3.1. Study Design
A home-based, randomized, single-blind and crossover trial included 14 adolescents aged 14­
18 years with type 1 diabetes. All participants were sent to their homes for 4 consecutive days 
with a different glycemic index breakfast. The insulin doses of the meals were calculated 
according to CC and FII methods. Test breakfasts with different GIs and insulin requirements 
calculated with different algorithms are as follows: High GI calculated by CC (CHGI), low GI 
calculated by CC (CLGI), high GI calculated by FII (FHGI) and low GI calculated by FII 
(FLGI). The order of the test meals and insulin algorithms was determined by using a computer- 
generated randomization sequence before recruitment. The test diets prepared by the dietitian 
were given to the participants by the diet company before the test day. Test meals were served 
as a breakfast after 8-hours fasting and participants were asked to consume the meal in full, 
within 20 min. The breakfast plates were collected and weighed after the test day. On the day 
before each test meal, participants were instructed to eat an evening snack meal at 22:00 h and 
to refrain from eating and/or drinking (except for water) and/or doing any physical activity 
beyond that of their typical daily activities. Participants started to consume test meals at 07.00 
h. They were asked not to consume any food other than breakfast for postprandial 240 min. 
Participants maintained their normal activity levels during the study days. The classification of 
meals according to insulin dose calculation methods is shown in the Figure 1.
This study was conducted according to the guidelines laid down in the Declaration of Helsinki. 
The Clinical Research Ethics Committee of the Erciyes University approved the protocol 
(2018/607) on 21 November 2018, and all participants gave written informed consent.

3.2. Participants
All participants underwent a detailed physical examination by the pediatric endocrinologist 
before included in the study. Fourteen adolescents with type 1 diabetes who attended the 
outpatient clinic of the Pediatric Endocrinology, at the Child Hospital of Erciyes University, 
Kayseri, Turkey were selected on the basis of the following criteria: aged between 14-18 years 
adolescents, type 1 diabetes diagnosed for at least one year (1, 8, 11, 14-16), performing self- 
monitoring of blood glucose and doses of insulin at least four times daily (17, 18), HbA1c < 
9.6% for the last three months (19), negative fasting C-peptide (<0.1 nmol/L) (20), total daily 
insulin use of > 0.5 U/kg (19), World Health Organization BMI/age z-score of -1 to below 3 
(21). Exclusion criteria included complications of diabetes or other medical conditions 
including celiac disease (11, 13), treatment with oral hypoglycaemic agents (11), food allergies, 
intolerances, or eating disorder (1, 8, 17), intestinal malabsorption (22), delayed gastric 
emptying (20), viral or bacterial infection, physical or mental disability (22, 23), clinical 
condition related to impaired digestive system such as cystic fibrosis (19, 22).
Figure 1. The classification of meals according to insulin dose calculation methods
3.3. Test Meals
The energy content of the test meals was calculated according to the recommended energy 
requirement for adolescents between the ages of 14-18 in Turkey’s Dietary Guidelines. In 
addition, according to the principles of adequate and balanced nutrition, breakfast meals should 
meet 1/4-1/5 of daily energy requirement (24, 25). Therefore, the energy of the test meals was 
determined about 560 kcal. The energy, carbohydrate, protein, fat and FII of the test meals were 
the same; GI were different. The participants were given 75 ml of whole milk, 22 g hot dog, 60 
g cheddar cheese, 75 g white bread and 8 g seedless raisins for breakfast with high glycemic 
index; 30 g Ezine cheese, 65 g boiled eggs, 13 g peanut, 20 g whole grain bread, 55 g apple, 
185 g strawberry yogurt and 100 ml skimmed milk for breakfast with low glycemic index. The 
energy and macronutrient composition of the test meals is given in the Table 1.
GI and FII of foods in test meals were estimated by using the GI and FII for 1000-kJ portions 
of foods tables published by Bao et al. (26), with glucose as the reference food. The average 
meal GI and FII were calculated as follows (27):

„  
l n  
Sa=ıGIa x AvCHOa x Frequencya 
Sa=ıIIa x Energya x Frequencya
Meal GI = — —---------------------------------------Meal II = ——-------------------------------------
i a = ıAvCHOa x Frequencya 
^ a =1 Energya x Frequencya
Meal with high glycemic 
index
Meal with low glycemic 
index
Total energy (kcal)
555
561
Carbohydrate (g)
61.8
61.6
Carbohydrate (%)
45
45
Protein (g)
22.6
22.3
Protein (%)
17
17
Fat(g)
23.1
23.3
Fat (%)
38
38
Glycemic Index
64
35
Food Insulin Index
45
45
Table 1. The energy and macronutrient composition of the test meals
3.4. Calculation of insulin dose of test meals:
The insulin dose of the meals was calculated by 2 different methods.
3.4.1. Carbohydrate Counting
Insulin carbohydrate ratio (ICR) was determined for each participant. The participant’s 
individualized ICR, expressed as insulin units per 15 g carbohydrate portion, was used to 
calculate insulin dose (28, 29).
3.4.2. Food Insulin Index
Insulin dose was calculated from the Food Insulin Demand (FID). The FID is the mathematical 
product of the FII and the energy content (kJ) per serving divided by 1000 (FID = FII x kJ per 
serving/ 1000). The FID was scaled up by a factor of 100/59 (FID of 1000 kJ of pure 
glucose/grams of carbohydrate in 1000 kJ of pure glucose) so that insulin could be dosed in the 
same ratio as each participants’ individualized ICR (1, 11)
4. Measurement of blood glucose
Postprandial glycemia was measured for 240 min with both continuous glucose monitoring and 
glucometer. Participants attended the clinic prior one day of the study for insertion of CGM 
(Medtronic iPro2) (11). CGM data was download and reviewed after completion of the study. 
Capillary blood testing was performed just before breakfast (t=0 min) and at time points 30, 60, 
90, 120, 150, 180, 210 and 240 min after the meal with glucometer (Accu-Check Performa 
Nano) (8, 11). Participants were also required to keep these blood glucose values.

Hypoglycaemic event, defined as a blood glucose level drop to < 3.9 mmol/l (30), confirmed 
on fingerstick. Data was excluded for the times after the participant had a hypoglycaemic event 
for the rest of the study period (11).
5. Anthropometric measurements
Body height and weight were measured using an automatic height gauge scale (DENSI GL150, 
Istanbul, Turkey) sensitive to 10-200 kg±50 g and 90-200 cm±1 mm. The measurements were 
made with the participants in the minimum clothing possible, without shoes, standing barefoot, 
keeping shoulders in a relaxed position, arms hanging freely and head in the Frankfort 
horizontal plane (31). BMI was calculated as weight (kg) divided by the square of height (m2) 
(31), and converted age- and sex-specific z-score according to WHO criteria (32).
6. Statistical Analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (version 
22.0; IBM SPSS Statistics) software. Data were expressed as the number (n) and percentage 
(%) for categorical variables, and means ± SDs, medians (25th-75th percentiles) for continuous 
variables. Normality was assessed using the Shapiro- Wilk test. Furthermore, continuous 
variables were examined for skewness and kurtosis, and log-transformed before analysis and 
reported back-transformed geometric means (G) ± standard error (S.E) when required (33). 
Differences between groups were tested using t-tests. The blood glucose profile during the 4-h 
postprandial period was quantified as area under the curve (AUC) calculated according to the 
trapezoidal rule. A one-way repeated measure was used to analyse between the comparable test 
conditions. For all statistical analyses, p values less than 0.05 were considered to have statistical 
significance (8).
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