Carbohydrates Under Target for Type 1 Diabetes Management

Recently, there has been an increased interest in limiting carbohydrates (CHO) intakes for improving long-term health. Low CHO (<30% energy from CHO) and very low CHO high fat (VLCHF; 10% CHO, 75% Lipid) diets are being advocated among people living with diabetes given their almost immediate favorable impact on post-prandial blood glucose levels and on hemoglobin A1c that have been reported by users. Adoption of these diets are met with reluctance by healthcare professionals due to the lack of information on their safety. Concerns include the impact on hypoglycemia frequency and glucagon response to hypoglycemia, diabetic ketoacidosis, lipid profile, liver function insulin dose adjustments when adopting them in the context of type 1 diabetes (T1D). Through a series of interviews, people with diabetes following a VLCHF reported that the lack of support from HCPs often leads to hiding the fact that they have adopted a VLCHF diet. This is an important source of concern that can lead to additional safety issues. The goal is to fill an important knowledge gap about the effectiveness, benefits and risks of low CHO and VLCHF diets for people with T1D. The primary objective is to compare the percentage of TIR of adults with T1D following a low-CHO diet or a VLCHF diet versus a control diet for 12 weeks. The secondary objectives are (1) to evaluate efficacy of glucagon in correcting hypoglycemia in the context of restricted carbohydrates intakes; (2) to evaluate changes in HbA1c at 12 weeks and glucose fluctuations and % of time in hypoglycemia at 6 weeks and 12 weeks of control diet, low-CHO diet or VLCHF diet; (3) to compare key cardiometabolic risk factors (body composition, blood lipids, blood pressure and liver inflammatory markers and function) at 6 weeks and 12 weeks of control diet, low-CHO diet or VLCHF diet; (4) to evaluate the effect of restrictive CHO diets (low-CHO and VLCHF) on the composition of the intestinal microbiota (optional).

Two weeks before the intervention phase, insulin dose optimization and revision of participants' knowledge on carbohydrates counting, hypo- and hyperglycemia prevention and treatment will be done with a nurse and a dietitian under a physician's supervision. Once to twice a week, participants will be contacted to review if glucose values are in target.

During the whole trial, blood glucose will be assessed by intermittent scanning Continuous Glucose Monitors (isCGM; Abbott's Freestyle-Libre glucose sensor). Participants will be asked to record or download, in their Freestyle Libre reader or in their insulin pump, their insulin doses being injected each day.

Two weeks before the intervention phase, participants will be asked to complete a 3-day food journal, using the Keenoa mobile application, with carbohydrates (CHO) content of food and blood glucose measures to optimize their insulin doses. Analysis of the food journal will allow us to quantify the participants' usual diet.

During visit 1, a short medical interview will be done to establish if the subject is eligible to participate in the study. A list of current medications, presence of complications, as well as comorbidities associated with their diabetes will be collected in their medical file during the visit with the endocrinologist.

Blood pressure (systolic and diastolic blood pressure) will be measured during all visits (visits 1 to 4).

Both resting metabolic rate and respiratory quotient will be measured after a 10-hour fast by indirect calorimetry. The test will be done twice, before (visit 2) and after (visit 4) the intervention phase.

Participants will be asked to complete a well-being questionnaire (nausea, fatigue, etc) during visits 2, 3 and 4.

Participants will be asked to complete a diet appreciation (appetite, fullness, etc) questionnaire during visits 3 and 4.

Participants will be asked to wear a pedometer (PiezoRxD) that will record their steps every day during the whole trial. Also, they will have to install Piezo: Achieve the Guidelines!, a free mobile application, on their smartphone or tablet. It will connect to their pedometer via bluetooth and will help the research assistant track their data remotely

Imaging of participants' liver will be done by MRI at the Centre Hospitalier de l'Université de Montréal (CHUM). The test will be done twice, before (visit 2) and after (visit 4) the intervention phase.

The glucagon efficiency test will be done twice, before (visit 2) and after (visit 4) the intervention phase. A subcutaneous insulin injection based on individual insulin correction factor will be given to induce hypoglycemia down to 3 mmol/L (based on plasma glucose). A subcutaneous injection of 300 µg of glucagon will be administered.

Lean body mass and fat mass will be measured by Dual Energy X-ray absorptiometry (DEXA). The DEXA test will be done twice, before (visit 2) and after (visit 4) the intervention phase.

Blood tests will be done to assess participants' diabetes control as well as to assess other biochemical markers (blood lipids as well as markers of inflammation and liver function). Blood will be collected and analyzed during all visits (visits 1 to 4).

Participants will be asked to collect and immediately freeze their stool sample until it is given to the study team (for intestinal microbiota composition analysis). This will be done three times during the study, during phase 1, between week 1 and 6 of phase 2 and between week 6 and 12 of phase 2.

During the whole trial, participants will be asked to keep a log of their hypoglycemia episodes, which are defined by the need to consume CHO. They will be asked to note the time, symptoms (including time taken for disappearance after treatment), capillary glucose measurement and the amount of CHO consumed.

During the intervention phase, participants will be asked to measure their ß-hydroxybutarate level (mmol/L) with their Abbott's Freestyle-Libre scanner at least twice per week before breakfast. Participants will be asked to check their ketone bodies for sensor or capillary glucose levels exceeding 15 mmol/l, when their sensor indicates high without a specific glucose value and when they have symptoms of ketoacidosis (regardless of glucose reading).

During the whole dietary intervention phase (phase 2), participants will confirm that they have followed their menus by taking before and after pictures of their meals every day and indicating the percentage of their meal consumed (25-50-75-100%) via the Keenoa mobile application.

After administration of subcutaneous insulin; At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 5 hours

After administration of glucagon; At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 5 hours

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

During DEXA-scan : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 15 minutes

At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During blood test : At baseline (day 1), before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

During indirect calorimetry test : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 30 minutes

During indirect calorimetry test : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 30 minutes

During MRI : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 30 minutes

During MRI : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 30 minutes

During MRI : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 30 minutes

During MRI : At beginning (week 3) and end (week 14) of the diet intervention, each test lasts approximately 30 minutes

The World Health Organisation- Five Well-Being Index (WHO-5) : I have felt cheerful in good spirits, I have felt calm and relaxed, I have felt active and vigorous, I woke up feeling fresh and rested, My daily life has been filled with things that interest me. The raw score is calculated by totaling the figures of the five answers (0 = At no time to 5 = All of the time). The raw score ranges from 0 to 25, 0 representing worst possible and 25 representing best possible quality of life.

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

ß-hydroxybutarate level (mmol/L) measured using ketometer integrated in Abbott's Freestyle-Libre scanner

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Before diet intervention (week 3), halfway the diet intervention (week 8) and at the end of the diet intervention (week 14)

Three days during the first 2 weeks (3-day food journal) and from beginning (week 3) to end (week 14) of diet intervention

Three days during the first 2 weeks (3-day food journal) and from beginning (week 3) to end (week 14) of diet intervention

Three days during the first 2 weeks (3-day food journal) and from beginning (week 3) to end (week 14) of diet intervention

Three days during the first 2 weeks (3-day food journal) and from beginning (week 3) to end (week 14) of diet intervention

Inclusion Criteria: Men and women > 18 years old Duration of T1D > 12 months On intensive insulin therapy Own a smartphone or tablet to use two mobile applications for nutritional and physical activity tracking: Keenoa and Piezo: Achieve the Guidelines! Exclusion Criteria: Already following a low-CHO diet (<30% CHO) Type 2 diabetes or other form of diabetes Known gastroparesis (clinical diagnosis) Advanced kidney disease (eGFR < 50 mL/min) Known significant liver disease (e.g. cirrhosis, active hepatitis, liver transplantation) Recent (<6 months) major cardiovascular event (e.g. myocardial infarction, cerebrovascular accident, major revascularization, etc.) Pregnancy (ongoing or planned in the next 6 months) Breastfeeding (ongoing) Recent severe hypoglycemia episodes (BG <2.8 mmol/L or assistance from a third party) or ketoacidosis (<6 weeks) Claustrophobia or presence of metal devices/implants in the body Recent (<6 weeks) or planned (next 6 months) modification in insulin treatment Recent (<6 weeks) or planned (next 6 months) modification in cardiometabolic drugs for blood pressure and/or lipids. These drugs must remain stable all along the trial Off label adjunct therapy with SGLT-2 inhibitors (Forxiga®, Invokana® or Jardiance®) Recent (<6 weeks) or planned (next 6 months) modification of adjunct therapy (Metformin, Glumetza®, Victoza®, Trulicity® and Ozempic®)