GIdiet: Effect of Dietary Glycemic Index on Beta-cell Function

• Sponsor: Seattle Institute for Biomedical and Clinical Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT01386645
• Collaborator: VA Puget Sound Health Care System (U.S. Fed)
• Enrollment: 56
• Location: 1
• Arms: 3
• Duration (Months): 97
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The study will determine if increasing the highs and lows of blood glucose levels (glycemic variability) impairs insulin secretion in people with impaired glucose tolerance and/or impaired fasting glucose who are at risk for developing type 2 diabetes. Furthermore, the study will determine whether changes in beta-cell function are associated with glycemic variability and whether they are mediated by oxidative stress. To decrease or increase glycemic variability the study will provide subjects with special diets containing either low or high glycemic index foods respectively for 4 weeks. To determine if oxidative stress is a mediator, subjects on the high glycemic index diet will take either placebo or the anti-oxidant N-acetylcysteine. The study will address the hypothesis that increased glycemic variability results in increased oxidative stress and thereby exacerbates beta-cell dysfunction in individuals with impaired glucose tolerance and/or impaired fasting glucose. The findings may have important implications for the development of effective strategies aimed at the prevention and treatment of type 2 diabetes. In addition, understanding the contribution of dietary glycemic index to beta-cell dysfunction in subjects with pre-diabetes may have a significant public health impact, including changes to dietary counseling and promotion of healthier eating patterns.

Condition or Disease	Intervention/Treatment	Phase
Impaired Glucose Tolerance; Oxidative Stress; Prediabetes; Impaired Fasting Glucose	Other: low glycemic index (LGI) diet; Other: high glycemic index (HGI) diet plus placebo (PLAC); Drug: high glycemic index diet plus N-acetylcysteine	N/A

Detailed Description

Type 2 diabetes is a major health problem in the United States affecting millions of people. It is caused by failure of the pancreatic beta-cells to secrete enough insulin resulting in high blood glucose levels. People with impaired glucose tolerance (IGT) and impaired fasting glucose have elevated glucose levels and are at increased risk for progressing to type 2 diabetes. The long-term objectives of this research are to better understand the factors that contribute to the loss of beta-cell function and impaired insulin secretion. High glucose levels have been shown to impair beta-cell function by causing oxidative stress, and oscillating high glucose levels increase oxidative stress even more than continuous high glucose. Diets containing foods with a high glycemic index (GI) increase the glycemic load (GL) of the diet and post-prandial glucose levels. Therefore, high GL (HGL) diets could be potentially damaging to the beta-cell by increasing glucose fluctuations and oxidative stress. Conversely, low GL (LGL) diets may be beneficial. The study explores the hypothesis that increased glycemic variability results in increased oxidative stress and thereby exacerbates beta-cell dysfunction in people with pre-diabetes.

Specific Aim 1: Determine if a HGL diet worsens and a LGL diet improves beta-cell function compared to a baseline control diet in subjects with pre-diabetes.

Specific Aim 2: Determine if increased glycemic variability on the HGL diet is associated with decreased beta-cell function and conversely if decreased glycemic variability on the LGL diet is associated with improved beta-cell function in subjects with pre-diabetes.

Specific Aim 3: Determine if oxidative stress induced by a HGL diet mediates decreases in beta-cell function by determining if 1) systemic markers of oxidative stress are associated with beta-cell function; 2) if the relationship between glycemic variability and beta-cell function is at least partially explained by oxidative stress; and 3) the anti-oxidant N-acetylcysteine (NAC) prevents decreases in beta-cell function on a HGL diet.

Study design: The study will be a randomized, parallel-design feeding study in men and women with pre-diabetes. Subjects will be randomly assigned to one of 3 separate arms (n=20/arm):

1. 4 weeks on a LGL diet (GI<35); 2) 4 weeks on a HGL diet (GI>70) + placebo twice daily; or
2. 4 weeks on a HGL diet (GI>70) + NAC 1200 mg twice daily. Subjects will be studied after a 2 week baseline control diet with a moderate glycemic load (GI 55-58) for comparison and all diets will be weight stable with the same macronutrient composition (55% carbohydrate/30% fat/15% protein). Beta-cell function will be assessed by both a frequently sampled intravenous glucose tolerance test and a meal test. Glycemic variability will be assessed by a Continuous Glucose Monitoring System and glycemic control by fructosamine. Markers of oxidative stress will be measured.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Effect of Dietary Glycemic Index on Beta-cell Function
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Aug 1, 2019
• Actual Study Completion Date: Aug 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Low GI diet low glycemic index diet	Other: low glycemic index (LGI) diet; Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab; Other Names: LGI
Placebo Comparator: High GI diet placebo high glycemic index diet plus placebo	Other: high glycemic index (HGI) diet plus placebo (PLAC); Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.; Other Names: HGI/PLAC
Active Comparator: High GI diet NAC high glycemic index diet plus N-acetylcysteine	Drug: high glycemic index diet plus N-acetylcysteine; Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.; Other Names: Diet N-acetylcysteine NAC

Outcome Measures

Primary Outcome Measures

1. Disposition Index [4 weeks]

   The disposition index generated from an intravenous glucose tolerance test (insulin sensitivity x the acute insulin response to intravenous glucose) is a measure of beta-cell function.

Secondary Outcome Measures

1. Urine F2alpha Isoprostanes [4 weeks]

   Fasting urine F2alpha isoprostane/Cr ratio. Urine isoprostanes were measured by ELISA (Oxford Biomedical Research).

2. Glycemic Variability [4 weeks]

   Glycemic variability as measured by the standard deviation (SD) of the glucose levels from the iPro continuous glucose monitoring system (CGMS)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• impaired glucose tolerance (2 hour glucose 140-200 mg/dl after a standard 75 grams oral glucose tolerance test [OGTT]) or

• fasting glucose 100-115 mg/dl and 2 hour glucose > 100 mg/dl after a standard OGTT

Exclusion Criteria:

• diabetes or taking diabetes medications

• fasting glucose >115 mg/dl

• alanine aminotransferase (ALT) >1.5 times the upper limit of normal

• hematocrit <33%

• serum creatinine >1.5 men or >1.3 women

• multiple food allergies or intolerances

• other serious medical or inflammatory conditions

• pregnancy or lactation

• smoke or use tobacco

• take medications that affect insulin sensitivity and secretion (niacin, diabetes medications or glucocorticoids) or inflammation (anti-inflammatories such as ibuprofen, naprosyn, aspirin)

• significant gastroesophageal reflux (heartburn), swallowing problems or stomach ulcers, including those taking medication for these indications

• taking or having taken another investigational drug within the past 30 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Puget Sound Health Care System	Seattle	Washington	United States	98108

Sponsors and Collaborators

• Seattle Institute for Biomedical and Clinical Research
• VA Puget Sound Health Care System

Investigators

• Principal Investigator: Kristina M Utzschneider, MD, VA Puget Sound Health Care System

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 2, 2014

More Information

Publications

None provided.

• Responsible Party: Seattle Institute for Biomedical and Clinical Research
• ClinicalTrials.gov Identifier: NCT01386645
• Other Study ID Numbers: 1R01DK092568-01
• First Posted: Jul 1, 2011
• Last Update Posted: Aug 12, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Seattle Institute for Biomedical and Clinical Research: impaired glucose tolerance; prediabetes; dietary glycemic index; beta-cell function; insulin secretion; oxidative stress; glycemic variability
• Additional relevant MeSH terms: Prediabetic State; Glucose Intolerance; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

Arm/Group Title	Low GI Diet	High GI Diet Placebo	High GI Diet NAC
Arm/Group Description	low glycemic index diet low glycemic index diet: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab	high glycemic index diet plus placebo high glycemic index diet plus placebo: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.	high glycemic index diet plus N-acetylcysteine high glycemic index diet plus N-acetylcysteine: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.
Period Title: Overall Study
STARTED	18	19	19
COMPLETED	18	18	17
NOT COMPLETED	0	1	2

Baseline Characteristics

Arm/Group Title	Low GI Diet	High GI Diet Placebo	High GI Diet NAC	Total
Arm/Group Description	low glycemic index diet low glycemic index diet: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab	high glycemic index diet plus placebo high glycemic index diet plus placebo: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.	high glycemic index diet plus N-acetylcysteine high glycemic index diet plus N-acetylcysteine: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.	Total of all reporting groups
Overall Participants	18	18	17	53
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (7.0)	50.6 (10.3)	51.2 (11.0)	53.0 (9.9)
Sex: Female, Male (Count of Participants)
Female	8 44.4%	9 50%	10 58.8%	27 50.9%
Male	10 55.6%	9 50%	7 41.2%	26 49.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 16.7%	3 16.7%	2 11.8%	8 15.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 11.1%	4 22.2%	8 47.1%	14 26.4%
White	13 72.2%	11 61.1%	7 41.2%	31 58.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%	18 100%	17 100%	53 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.5 (4.7)	32.4 (6.4)	32.7 (8.0)	32.5 (6.3)

Outcome Measures

1. Primary Outcome

Title	Disposition Index
Description	The disposition index generated from an intravenous glucose tolerance test (insulin sensitivity x the acute insulin response to intravenous glucose) is a measure of beta-cell function.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

1 participant in the LGI group ate before the second IVGTT and was excluded. One participant in the HGI/PLAC group could not get a second IV and we were unable to perform the IVGTT.

Arm/Group Title	Low GI Diet	High GI Diet Placebo	High GI Diet NAC
Arm/Group Description	low glycemic index diet low glycemic index diet: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab	high glycemic index diet plus placebo high glycemic index diet plus placebo: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.	high glycemic index diet plus N-acetylcysteine high glycemic index diet plus N-acetylcysteine: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.
Measure Participants	17	17	17
Median (95% Confidence Interval) [unitless]	708	793	791

2. Secondary Outcome

Title	Urine F2alpha Isoprostanes
Description	Fasting urine F2alpha isoprostane/Cr ratio. Urine isoprostanes were measured by ELISA (Oxford Biomedical Research).
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Adults with prediabetes after 4 weeks on study interventions.

Arm/Group Title	Low GI Diet	High GI Diet Placebo	High GI Diet NAC
Arm/Group Description	low glycemic index diet low glycemic index diet: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab	high glycemic index diet plus placebo high glycemic index diet plus placebo: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.	high glycemic index diet plus N-acetylcysteine high glycemic index diet plus N-acetylcysteine: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.
Measure Participants	18	18	17
Median (95% Confidence Interval) [ng/mg]	2.51	3.35	3.43

3. Secondary Outcome

Title	Glycemic Variability
Description	Glycemic variability as measured by the standard deviation (SD) of the glucose levels from the iPro continuous glucose monitoring system (CGMS)
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Adults with prediabetes with useable iPro CGMS data after the 4 week intervention.

Arm/Group Title	Low GI Diet	High GI Diet Placebo	High GI Diet NAC
Arm/Group Description	low glycemic index diet low glycemic index diet: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab	high glycemic index diet plus placebo high glycemic index diet plus placebo: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.	high glycemic index diet plus N-acetylcysteine high glycemic index diet plus N-acetylcysteine: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.
Measure Participants	16	17	16
Mean (Standard Error) [mg/dl]	14.20 (1.03)	19.67 (1.57)	17.69 (1.56)

Adverse Events

Time Frame	6 weeks
Adverse Event Reporting Description	Participants were asked about any problems related to their general health, heart, lungs, gastrointestinal system, neurologic system, urinary system and musculoskeletal system at the screening visit and at the end of the control and intervention diets using a systematic screening form. Adverse events were also reported by participants as they occurred.
Arm/Group Title	Low GI Diet		High GI Diet Placebo		High GI Diet NAC
Arm/Group Description	low glycemic index diet low glycemic index diet: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable low glycemic index diet (glycemic index <35) for 4 weeks with all food provided by the Human Nutrition Lab		high glycemic index diet plus placebo high glycemic index diet plus placebo: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take placebo capsules (matching for active N-acetylcysteine (NAC) in arm 3) twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.		high glycemic index diet plus N-acetylcysteine high glycemic index diet plus N-acetylcysteine: Following a 2 week medium glycemic index control diet (glycemic index 50-55), subjects will be provided with a weight stable high glycemic index diet (glycemic index >70) for 4 weeks, all food provided by the Human Nutrition Lab. They will take N-acetylcysteine (NAC) two 600 mg capsules twice daily for the 4 weeks on the high GI diet. The NAC vs. placebo arms (arms 2 and 3) will be double-blinded.
All Cause Mortality
	Low GI Diet		High GI Diet Placebo		High GI Diet NAC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)		0/17 (0%)
Serious Adverse Events
	Low GI Diet		High GI Diet Placebo		High GI Diet NAC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Low GI Diet		High GI Diet Placebo		High GI Diet NAC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		1/18 (5.6%)		0/17 (0%)
Gastrointestinal disorders
gastroenteritis	1/18 (5.6%)	1	0/18 (0%)	0	0/17 (0%)	0
Musculoskeletal and connective tissue disorders
cracked tooth	0/18 (0%)	0	1/18 (5.6%)	1	0/17 (0%)	0

Limitations/Caveats

Some of the iPro CGMS devices failed to record or were dislodged. Thus, the number of participants with useable data for the CGMS variability data is less than the total enrolled.

More Information

Certain Agreements

Principal Investigators are NOT 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.