The Impact of Macronutrient Composition on Glucose Dynamics in Persons With Type 1 Diabetes (HiLo21)

• ClinicalTrials.gov Identifier: NCT05268705
• Recruitment Status: Completed
• First Posted: March 7, 2022
• Last Update Posted: January 9, 2023
• Sponsor: Steno Diabetes Center Copenhagen
• Collaborator: Swansea University
• Information provided by (Responsible Party): Steno Diabetes Center Copenhagen

Tracking Information

• First Submitted Date: January 31, 2022
• First Posted Date: March 7, 2022
• Last Update Posted Date: January 9, 2023
• Actual Study Start Date: February 3, 2022
• Actual Primary Completion Date: November 8, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 24, 2022): The primary endpoint is the difference between study arms in difference from start to end plasma glucose concentration during 45 min fasted cycling (assessed by YSI (Yellow Spring Instruments 2900 STAT Plus)). [ Time Frame: 45 min ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 24, 2022)

• Mean CGM glucose level assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Time spent < 3.9 mmol/l assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Time spent < 3.0 mmol/l assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Time spent 3.9-10.0 mmol/l assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Time spent > 10.0 mmol/l assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Time spent > 13.9 mmol/l assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Plasma glucose coefficient of variation assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Standard deviation assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Number of hypoglycemia events (< 3.9 mmol/l) of at least 15 minutes duration assessed by CGM during diet interventions [ Time Frame: 7 days ]
• Energy expenditure after each diet intervention assessed by indirect calorimetry [ Time Frame: 15 min ]
• Respiratory exchange ratio after each diet intervention assessed by indirect calorimetry [ Time Frame: 15 min ]
• Carbohydrate oxidation rate after each diet intervention assessed by indirect calorimetry [ Time Frame: 15 min ]
• Fat oxidation rate after each diet intervention assessed by indirect calorimetry [ Time Frame: 15 min ]
• Mean plasma glucose assessed by YSI during cycling and observation phase 2 [ Time Frame: 135 min ]
• Plasma glucose nadir assessed by YSI during cycling and observation phase 2 [ Time Frame: 135 min ]
• Plasma glucose variation assessed by YSI during cycling and observation phase 2 [ Time Frame: 135 min ]
• Plasma glucose standard deviation assessed by YSI during cycling and observation phase 2 [ Time Frame: 135 min ]
• Number of hypoglycemia events (< 3.9 mmol/l) assessed by YSI during cycling and observation phase 2 [ Time Frame: 135 min ]
• Mean insulin during cycling and observation phase 2 [ Time Frame: 135 min ]
• Peak insulin during cycling and observation phase 2 [ Time Frame: 135 min ]
• Areal under the curve for insulin during cycling and observation phase 2 [ Time Frame: 135 min ]
• Energy expenditure assessed by indirect calorimetry during cycling and observation phase 2 [ Time Frame: 135 min ]
• Respiratory exchange ratio assessed by indirect calorimetry during cycling and observation phase 2 [ Time Frame: 135 min ]
• Carbohydrate oxidation rate assessed by indirect calorimetry during cycling and observation phase 2 [ Time Frame: 135 min ]
• Fat oxidation rate assessed by indirect calorimetry during cycling and observation phase 2 [ Time Frame: 135 min ]
• Plasma glucose peak assessed by YSI during observation phase 3 [ Time Frame: 120 min ]
• Time to plasma glucose peak assessed by YSI during observation phase 3 [ Time Frame: 120 min ]
• Time from glucagon administration to 1.1 mmol/l increase in plasma glucose assessed by YSI during observation phase 3 [ Time Frame: 120 min ]
• Change in plasma glucose from injection of glucagon to peak plasma glucose assessed by YSI during observation phase 3 [ Time Frame: 120 min ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Impact of Macronutrient Composition on Glucose Dynamics in Persons With Type 1 Diabetes
• Official Title: The Impact of Macronutrient Composition on Glucose Dynamics in Everyday Life and During Fasted Cycling in Persons With Type 1 Diabetes
• Brief Summary: A randomized, open-label, three-arm crossover study will be conducted. The aim of the study is to determine the effect of different isocaloric diet macronutrient compositions (High-carbohydrate-Low-fat-Low-protein (HCLFLP), Low-carbohydrate-High-fat-Low-protein (LCHFLP), Low-carbohydrate-Low-fat-High-protein (LCLFHP)) on plasma glucose dynamics in everyday life and during fasted exercise in persons with type 1 diabetes. Our hypothesis is that a HCLFLP diet reduce the decrease in plasma glucose from start to end of fasted exercise compared with a LCHFLP diet. Secondary a LCHFLP compared with a LCLFHP diet does not reduces the decrease in plasma glucose from start to end of fasted exercise. The current study will contribute with new knowledge about the importance of the compositions of a low-carbohydrate diet on glucose dynamics and the influence on plasma glucose during and after cycling in fasted state.

Detailed Description

Background:

In order to increase time, spend in euglycemia ranges many persons with type 1 diabetes choose to follow a low-carbohydrate diet. However, to date strong evidence on the effects of low-carbohydrate diets in persons with type 1 diabetes is lacking with even less evidence pertaining around physical activity. Our impression is that many persons with type 1 diabetes follow a low-carbohydrate diet on their own initiative despite published available evidence is sparse. This emphasizes the need for more clinical trials that investigates the glycemic impact of low-carbohydrate diets.

The current guidelines for glucose management during exercise focus on carbohydrate intake and reduction of bolus and/or basal insulin immediately before, during and after exercise. The guidelines only briefly describe low-carbohydrate diet and do not describe matters concerning exercise in fasted state, because of lack of evidence in the field. Exercise in fasted state may be preferable for persons with type 1 diabetes since it increases lipid oxidation and is associated with better glucose stability than nonfasted exercise. Furthermore exercise in fasted state do not increase the risk of hypo- or hyperglycemia compared with a non-exercise control day.

Dietary carbohydrate intake might affect the hepatic glucose response. We will use glucagon as a tool to evaluate the hepatic glucose response after the three different diets.

The current study will contribute new knowledge about the importance of the compositions of a low-carbohydrate diet on glucose dynamics and the influence on plasma glucose during and after cycling in fasted state. In addition, the study will detail the importance of diet carbohydrate content on hepatic glucose response.

Study design:

A randomized, open-label, three-arm crossover study will be conducted, where the participants will serve as their own controls. The participants will complete one screening visit and three different 7-day diet interventions ending with an in-clinic study visit at day 8. The diets will be isocaloric and based on individual energy needs. The compositions will be a HCLFLP, LCHFLP, and a LCLFHP diet. The diet interventions will be in random order and there will be a washout period of 5-35 days.

Diet interventions:

Within a week before day 1 of the diet interventions, the participants must meet at Steno Diabetes Center Copenhagen to be instructed about the forthcoming diet intervention and undergo a physical extermination including weight-, blood pressure- and heart rate meassurement, blood sample collection (albumin, estimated glomerular filtration rate (eGFR), total cholesterol, VLDL, LDL HDL and triglycerides) and a urine sample collection (u-albumin-creatinine-ratio).

The participants must attach and start to use a CGM system the day before the start of the diet interventions (day 0) and a ActiGraph activity sensor in the morning of day 1 of diet interventions. The participants must wear the CGM and activity sensor until the end of the study visit at day 8.

Study visits:

At day 8 the participants must meet in the morning after an overnight fast at Steno Diabetes Center Copenhagen for the study visits. Except for the difference in content of the diets prior to the study visits, the study visits are identical.

After resting for 90 minutes (Observation phase 1), the participants must perform 45 min of cycling on an ergometer bike equaling to 60 % of their peak oxygen consumption or until hypoglycemia (plasma glucose < 3.9 mmol/l) or unbearable symptoms of hypoglycemia (Cycling phase). After cycling the participants are observed for 90 minutes or until hypoglycemia (< 3.9 mmol/l) or unbearable symptoms of hypoglycemia while resting (Observation phase 2). If plasma glucose drops < 3.9 mmol/l or if unbearable symptoms of hypoglycemia occurs during cycling, observation phase 2 or if hypoglycemia (< 3.9 mmol/l) or unbearable symptoms of hypoglycemia has not occurred after 90 min of observation phase 2 150 μg glucagon is given subcutaneously. From injection of glucagon the observation 3 phase begins. The participants will be observed 120 minutes after injection of glucagon. A mixed meal will be served before the participants leave the research facility.

Thoughout the study visits the participants must use their insulin pump. The basalrate will be adjusted according to international guidelines. Blood samples for analyses of glucose, lactate, insulin, glucagon, GLP-1, GIP, ketones, inflammatory markers, cortisol, free fatty acids, growth hormone, albumin, estimated glomerular filtration rate (eGFR), total cholesterol, VLDL, LDL HDL and triglycerides will be drawn. Indirect calorimetry will be performed before, during and after exercise and after injection of glucagon to meassure energy expenditure, respiratory exchange ratio and carbohydrate and lipid oxidation rates. The Borg scale will be used to assess percieved exertion during exercise.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: type1diabetes

Intervention

• Other: 7-day diet
  The participants must follow a 7-day high-carbohydrate-low-fat-low-protein diet before the inclinic study visit at day 8. The in-clinic study visits are identical for all the three study arms.
• Other: 7-day diet
  The participants must follow a low-carbohydrate-high-fat-low-protein diet before the inclinic study visit at day 8. The in-clinic study visits are identical for all the three study arms.
• Other: 7-day diet
  The participants must follow a low-carbohydrate-low-fat-high-protein diet before the inclinic study visit at day 8. The in-clinic study visits are identical for all the three study arms.

Study Arms

• Active Comparator: High-carbohydrate-low-fat-low-protein diet
  Intervention: Other: 7-day diet
• Active Comparator: Low-carbohydrate-high-fat-low-protein diet
  Intervention: Other: 7-day diet
• Active Comparator: Low-carbohydrate-low-fat-high-protein diet
  Intervention: Other: 7-day diet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 24, 2022): 12
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: November 8, 2022
• Actual Primary Completion Date: November 8, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age ≥ 18 years
• Type 1 diabetes ≥ 5 years
• Insulin pump use ≥ 1 year
• Use of intermittently scanned continuous glucose monitoring (isCGM) or continuous glucose monitoring (CGM) ≥ 3 months
• HbA1c ≤ 69 mmol/mol (8.5%)
• Self-reported hypoglycemia awareness
• Exercising at least 30 minutes at moderate or vigorous intensity two times per week.

Exclusion Criteria:

• Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start
• Use of a hybrid closed-loop system
• Females who are pregnant, breast-feeding or intend to become pregnant during the study period
• Ischemic heart disease
• Severe asthma
• Other concomitant medical or psychological condition that according to the investigator's assessment makes the individual unsuitable for study participation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT05268705
• Other Study ID Numbers: H-21042230
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Steno Diabetes Center Copenhagen
• Original Responsible Party: Same as current
• Current Study Sponsor: Steno Diabetes Center Copenhagen
• Original Study Sponsor: Same as current
• Collaborators: Swansea University

Investigators

• Principal Investigator: Kirsten Nørgaard, Professor; Steno Diabetes Center Copenhagen, Clinical Reseach, Diabetes Technology Research

• PRS Account: Steno Diabetes Center Copenhagen
• Verification Date: January 2023