Effect of Dietary Glycemic Index on Beta-cell Function
Condition: Impaired Glucose Tolerance; Oxidative Stress; Prediabetes; Impaired Fasting Glucose
MeSH terms: Prediabetic State; Glucose Intolerance
Study type: Interventional

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.
    

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
      3) 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.
    

Intervention name(s): low glycemic index (LGI) diet; high glycemic index (HGI) diet plus placebo (PLAC); high glycemic index diet plus N-acetylcysteine
Intervention type(s): Other; Other; Drug
Intervention description(s): 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; 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.; 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 intervention name(s): LGI; HGI/PLAC; Diet; N-acetylcysteine; NAC
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: impaired glucose tolerance; prediabetes; dietary glycemic index; beta-cell function; insulin secretion; oxidative stress; glycemic variability