Dietary Glycemic Index, Brain Function and Food Intake in Patients With Type 1 Diabetes Mellitus

• Sponsor: Boston Children's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02772783
• Collaborator: Beth Israel Deaconess Medical Center (Other), Brigham and Women's Hospital (Other)
• Enrollment: 15
• Location: 1
• Arms: 3
• Duration (Months): 22
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Processed carbohydrates cause rapid changes in blood sugar and have been associated with overeating and obesity. We have shown that test meals high in processed carbohydrate affect brain areas involved in addiction, craving and overeating. It is unknown whether the changes in blood sugar or the associated higher insulin levels mediate this brain activation and its likely adverse effects.

Answering this question is important for patients with type 1 diabetes who have elevated risks of obesity and disordered eating: If blood sugar is the causal mechanism, optimal insulin coverage should be protective. If insulin is the causal mechanism, however, a diet high in processed carbohydrate could predispose to overeating and weight gain, as this diet requires higher insulin doses.

To disentangle these factors, we will study brain activation and relevant blood markers in 15 men with diabetes. In 4 sessions, we will examine meals with differential carbohydrate properties while giving insulin infusions.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Other: high GI meal; Other: low GI meal; Drug: euglycemic insulin clamp; Drug: primed-variable insulin infusion	N/A

Detailed Description

A total of 15 male participants (age 18-45) with T1DM will be recruited. Participants will be enrolled in the study for a total of 1-3 months, and participate in a pre-test visit and three test visits, each after a 10-12-hr overnight fast. Participants will be instructed to consume their regular, weight maintaining diet between visits.

At the pre-test visit, the study director or PI will meet participants, confirm eligibility and obtain informed consent. Participants will receive a low glycemic index (GI) meal with optimal iv insulin coverage using a negative feedback algorithm to maintain euglycemia (euglycemic clamp). Insulin requirement will be quantified. At some time during the visit, participants will present to the BIDMC research imaging facility for a practice MRI session, during which they will undergo a brief imaging sequence to get accustomed to the scanning process and eliminate anxiety as a confounder of imaging data.

At each of 3 test visits, one of the following experimental conditions will be applied in a randomized, blinded cross-over design: (a) high GI meal with euglycemic clamp, (b) low GI meal with euglycemic clamp, (c) high GI meal with primed-variable insulin infusion at the rate established during the pre-test visit. After steady state is established, baseline laboratory evaluation and MRI imaging will be obtained, followed by the test meal. Imaging will be repeated at 1 and 4 hours postprandial. Blood samples for pertinent metabolic and hormonal parameters will be obtained every 30 minutes. Each test-visit concludes with a standard weighed meal to quantify ad-libitum intake.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Dietary Glycemic Index, Brain Function and Food Intake in Patients With Type 1 Diabetes Mellitus
• Study Start Date: Jul 1, 2016
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: high GI meal, euglycemic insulin clamp A nutritional shake with high GI will be consumed. Regular insulin will be administered intravenously according to a negative feedback algorithm to maintain euglycemia.This condition results in euglycemia with high insulin levels.	Other: high GI meal; High and low GI liquid test meals are matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals will provide 25% of individual daily energy requirements as estimated by the Harris Benedict equation. A high glycemic index of ~90 is achieved by using corn syrup as a carbohydrate source.; Drug: euglycemic insulin clamp; Insulin will be given intravenously for 5 hours. During the entire clamp protocol, glucose levels will be measured every 5 minutes. A basal insulin infusion will be started at 80% of the patients insulin pump basal rate, and will be adjusted between 0.1 and 2.5 mU/kg•min, depending upon the patient's plasma glucose level in relation to the target range target of 90-100 mg/dl.
Experimental: high GI meal, fixed insulin infusion A nutritional shake with high GI will be consumed. Regular insulin will be administered intravenously at a rate previously established to maintain euglycemia after a low glycemic index meal. This condition results in moderate hyperglycemia with low insulin levels.	Other: high GI meal; High and low GI liquid test meals are matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals will provide 25% of individual daily energy requirements as estimated by the Harris Benedict equation. A high glycemic index of ~90 is achieved by using corn syrup as a carbohydrate source.; Drug: primed-variable insulin infusion; A primed-variable infusion of insulin will be administered at the rate established to achieve euglycemia after a low glycemic index meal. This is expected to result in moderate hyperglycemia as the high GI meal is associated with higher insulin requirements. For patient safety, glucose levels will be measured every 30 minutes. If glucose levels are > 400 mg/dl or < 60 mg/dl, insulin infusion will be adjusted to maintain glucose levels target of 60-400 mg/dl.
Active Comparator: low GI meal, euglycemic insulin clamp A nutritional shake with low GI will be consumed. Regular insulin will be administered intravenously according to a negative feedback algorithm to maintain euglycemia. This condition results in euglycemia with low insulin levels.	Other: low GI meal; High and low GI liquid test meals are matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals will provide 25% of individual daily energy requirements as estimated by the Harris Benedict equation. A low glycemic index of ~40 is achieved by using uncooked corn starch as a carbohydrate source.; Drug: euglycemic insulin clamp; Insulin will be given intravenously for 5 hours. During the entire clamp protocol, glucose levels will be measured every 5 minutes. A basal insulin infusion will be started at 80% of the patients insulin pump basal rate, and will be adjusted between 0.1 and 2.5 mU/kg•min, depending upon the patient's plasma glucose level in relation to the target range target of 90-100 mg/dl.

Outcome Measures

Primary Outcome Measures

1. Nucleus Accumbens Blood Flow [4 hrs postprandial]

   Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.

Secondary Outcome Measures

1. Nucleus Accumbens Blood Flow [1 hr postprandial]

   Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.

2. Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate [4 hrs postprandial]

   Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right dorsal caudate, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.

3. Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum [1 hr postprandial]

   Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right ventrolateral striatum, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.

4. Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation [4 hrs postprandial]

   Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures.

5. Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation [1 hr postprandial]

   Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures. Functional connectivity between Nucleus Accumbens and other brain areas was visually assessed.

Other Outcome Measures

1. Plasma Glucose Level [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes

2. Serum Insulin Level [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes

3. Serum Fatty Acids [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes

4. Plasma Ghrelin [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel

5. Plasma GLP-1 [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel

6. Plasma PYY [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel

7. Plasma CCK [0-4.5 hrs postprandial]

   analyzed as part of a metabolic hormone panel

8. Plasma Glucagon [0-4.5 hrs postprandial]

   blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel

9. Plasma Leptin [0-4.5 hrs postprandial]

   analyzed as part of a metabolic hormone panel

10. Metabolomics [0, 1 and 4 hrs postprandial]

    LC-MS/MS methodology using several chromatographic stationary phases for > 400 metabolites

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 1 diabetes for a minimum of 3 years

• BMI 20-35 kg/m2

• Use of insulin pump

• Willing and able to: Maintain weight and document for duration of the study

Exclusion Criteria:

• Insulin resistance (current insulin requirement > 1.5 U/kg/d)

• Insulin requirement < 0.5 unit/kg/day (cut-off for preserved beta-cell function)

• HbA1C ≥ 8.0%

• DKA within 2 months

• Frequent hypoglycemia (BG <50 mg/dl), > 3 times per week

• Fluctuations in body weight >10% over preceding year

• Smoking or illicit substance abuse

• High levels of physical activity (≥60 minutes per day, ≥ 4 days per week)

• Current weight loss diet

• Medical problems, medications or dietary supplements that may affect metabolism, insulin action, body weight, appetite, energy expenditure, or gastrointestinal absorption (e.g. celiac disease)

• Allergies to compounds or intolerance of the liquid meals

• MRI exclusion criteria

• Other conditions according to self-report that would prohibit participation based and researcher assessment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Boston Children's Hospital
• Beth Israel Deaconess Medical Center
• Brigham and Women's Hospital

Investigators

• Principal Investigator: Belinda S Lennerz, MD, PhD, Boston Children's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 26, 2016

More Information

Publications

None provided.

• Responsible Party: Belinda Lennerz, Instructor in Pediatric Endocrinology, Boston Children's Hospital
• ClinicalTrials.gov Identifier: NCT02772783
• Other Study ID Numbers: IRB-P00022176; IRB- 2016P000079
• First Posted: May 16, 2016
• Last Update Posted: Jun 18, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Belinda Lennerz, Instructor in Pediatric Endocrinology, Boston Children's Hospital: brain; fMRI; carbohydrate; insulin clamp; intake regulation; overweight; glycemic index
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc

Study Results

Participant Flow

Recruitment Details	Participants were recruited from the Boston Children's Hospital Diabetes Program and via postings in the surrounding medical area.
Pre-assignment Detail	Participants underwent a 5 hour pre-randomization visit to establish IV insulin requirement for a low GI test meal. Participants were positioned in the MRI scanner for a brief test sequence. Participants were excluded if they were unable to finish these pre-randomization procedures, or if they decided to not continue.

Arm/Group Title	High GI Matched Glucose - Low GI - High GI Matched Insulin	High GI Matched Insulin - Low GI - High GI Matched Glucose
Arm/Group Description	In a randomized cross-over design, a nutritional shake with high GI vs low GI was consumed with differential insulin coverage in the following order: High GI meal covered with IV insulin adjusted using a negative feedback algorithm to achieve euglycemia, resulting in hyperinsulinemia (experimental condition A); 1 day. - 1-week wash-out Low GI meal covered with IV insulin adjusted using a negative feedback algorithm to achieve euglycemia (comparison condition B); 1 day. - 1-week wash-out High GI meal with IV insulin matching the low GI meal, resulting in hyperglycemia (experimental condition C); 1 day. High and low GI liquid test meals were matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals provided 25% of individual daily energy requirements. Insulin was given intravenously for 5 hours. Glucose levels were measured every 5 minutes for insulin titration.	In a randomized cross-over design, a nutritional shake with high GI vs low GI was consumed with differential insulin coverage in the following order: High GI meal with IV insulin matching the low GI meal (as determined during the pre-randomization visit), resulting in hyperglycemia (experimental condition C); 1 day. - 1-week wash-out Low GI meal covered with IV insulin adjusted using a negative feedback algorithm to achieve euglycemia (comparison condition B); 1 day. - 1-week wash-out High GI meal covered with IV insulin adjusted using a negative feedback algorithm to achieve euglycemia, resulting in hyperinsulinemia (experimental condition A); 1 day. High and low GI liquid test meals were matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals provided 25% of individual daily energy requirements. Insulin was given intravenously for 5 hours. Glucose levels were measured every 5 minutes for insulin titration.
Period Title: Experimental Condition 1, 1 Day
STARTED	8	7
COMPLETED	8	7
NOT COMPLETED	0	0
Period Title: Experimental Condition 1, 1 Day
STARTED	8	7
COMPLETED	8	7
NOT COMPLETED	0	0
Period Title: Experimental Condition 1, 1 Day
STARTED	8	7
COMPLETED	8	7
NOT COMPLETED	0	0
Period Title: Experimental Condition 1, 1 Day
STARTED	8	7
COMPLETED	8	7
NOT COMPLETED	0	0
Period Title: Experimental Condition 1, 1 Day
STARTED	8	7
COMPLETED	8	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	In a randomized cross-over design, a nutritional shake with high GI vs low GI was consumed with differential insulin coverage: High GI meal covered with IV insulin to to achieve euglycemia, resulting in hyperinsulinemia (experimental condition A); 1 day. 1-week wash-out Low GI meal covered with IV insulin to achieve euglycemia (comparison condition B); 1 day. 1-week wash-out High GI meal with IV insulin matching the low GI meal, resulting in hyperglycemia (experimental condition A); 1 day. The order of experimental conditions A and B was randomized. High and low GI liquid test meals were matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals provided 25% of individual daily energy requirements. Insulin was given intravenously for 5 hours. Glucose levels were measured every 5 minutes for insulin titration. Because all participants completed all interventions, results are presented in aggregate for the entire study group.
Overall Participants	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	21 (1.6)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	15 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	15 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	15 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	15 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	21 (1.4)

Outcome Measures

1. Primary Outcome

Title	Nucleus Accumbens Blood Flow
Description	Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time Frame	4 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)	Low GI (LGI)	High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.
Measure Participants	15	15	15
right	1.13 (0.02)	1.16 (0.02)	1.15 (0.02)
left	1.21 (0.02)	1.18 (0.02)	1.18 (0.02)

2. Secondary Outcome

Title	Nucleus Accumbens Blood Flow
Description	Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time Frame	1 hr postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)	Low GI (LGI)	High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.
Measure Participants	15	15	15
right	1.12 (0.02)	1.16 (0.02)	1.11 (0.02)
left	1.20 (0.02)	1.19 (0.02)	1.14 (0.02)

3. Secondary Outcome

Title	Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate
Description	Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right dorsal caudate, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time Frame	4 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)	Low GI (LGI)	High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.
Measure Participants	15	15	15
Least Squares Mean (Standard Error) [ml/g/min per ml/g/min]	0.60 (0.01)	0.59 (0.01)	0.64 (0.01)

4. Secondary Outcome

Title	Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum
Description	Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right ventrolateral striatum, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time Frame	1 hr postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)	Low GI (LGI)	High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.
Measure Participants	15	15	15
Least Squares Mean (Standard Error) [ml/g/min per ml/g/min]	0.60 (0.01)	0.61 (0.01)	0.60 (0.01)

5. Secondary Outcome

Title	Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation
Description	Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures.
Time Frame	4 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)	Low GI (LGI)	High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.
Measure Participants	13	13	13
Least Squares Mean (Standard Error) [unite-less correlation]	0.26 (0.08)	0.24 (0.08)	0.25 (0.08)

6. Secondary Outcome

Title	Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation
Description	Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures. Functional connectivity between Nucleus Accumbens and other brain areas was visually assessed.
Time Frame	1 hr postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)	Low GI (LGI)	High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit. Interventions were presented in a cross-over design. Because all participants completed all interventions, results are presented by intervention.
Measure Participants	13	13	13
Least Squares Mean (Standard Error) [unite-less correlation]	0.36 (0.09)	0.15 (0.09)	0.15 (0.09)

7. Other Pre-specified Outcome

Title	Plasma Glucose Level
Description	blood samples will be obtained every 30 minutes
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Serum Insulin Level
Description	blood samples will be obtained every 30 minutes
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Serum Fatty Acids
Description	blood samples will be obtained every 30 minutes
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Plasma Ghrelin
Description	blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Plasma GLP-1
Description	blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Plasma PYY
Description	blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Plasma CCK
Description	analyzed as part of a metabolic hormone panel
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Plasma Glucagon
Description	blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Plasma Leptin
Description	analyzed as part of a metabolic hormone panel
Time Frame	0-4.5 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Metabolomics
Description	LC-MS/MS methodology using several chromatographic stationary phases for > 400 metabolites
Time Frame	0, 1 and 4 hrs postprandial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Enrollment through study completion (on average 2 months).
Arm/Group Title	High GI With Matched to Low GI Glucose (HGI HI)		Low GI (LGI)		High GI With Matched to Low GI Insulin (HGI LI)
Arm/Group Description	After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia.		After an overnight fast, a nutritional shake with low GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes, and Insulin was adjusted using a negative feedback algorithm to maintain euglycemia.		After an overnight fast, a nutritional shake with high GI was consumed. The shake provided 25% of daily calorie requirements with a macronutrient composition of 60% carbohydrate, 15% protein, 25% fat, and matched micronutrient profiles, physical properties, palatability and sweetness. Insulin was given intravenously to normalize blood glucose before the meal and for 5 hours postprandial. Blood glucose levels were measured every 5 minutes. Insulin was given at the same rates as determined appropriate for each participant during the pre-randomization visit or the LGI visit.
All Cause Mortality
	High GI With Matched to Low GI Glucose (HGI HI)		Low GI (LGI)		High GI With Matched to Low GI Insulin (HGI LI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	High GI With Matched to Low GI Glucose (HGI HI)		Low GI (LGI)		High GI With Matched to Low GI Insulin (HGI LI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	High GI With Matched to Low GI Glucose (HGI HI)		Low GI (LGI)		High GI With Matched to Low GI Insulin (HGI LI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		0/15 (0%)		1/15 (6.7%)
Cardiac disorders
Tachycardia	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
dizzyness	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.