Effect of Dietary Glycemic Index on Beta-cell Function (GIdiet)

• urine F2alpha isoprostanes [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  Measure of oxidative stress
• glycemic variability [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  Glycemic variability as measured by the SD of the glucose levels from continuous glucose monitoring

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 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. 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.

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) 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 IGT.

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 IGT.

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 IGT.

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 IGT. 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.

• Impaired Glucose Tolerance
• Oxidative Stress
• Prediabetes

• Other: 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
  Other Name: Diet
• Other: 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.
  Other Name: Diet
• 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

• Active Comparator: Low GI diet
  Low glycemic index diet (average glycemic index <35) for 4 weeks
  Intervention: Other: low glycemic index diet
• Placebo Comparator: High GI diet placebo
  High glycemic index diet (average glycemic index > 70) and placebo capsules 2 twice a day for 4 weeks
  Intervention: Other: high glycemic index diet plus placebo
• Active Comparator: High GI diet NAC
  Subjects will eat a high glycemic index diet (average glycemic index > 70) and take NAC 2 capsules twice a day for 4 weeks.
  Intervention: Drug: high glycemic index diet plus N-acetylcysteine

Inclusion Criteria:

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

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

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• VA Puget Sound Health Care System