Effect of Dietary Glycemic Index on Beta-cell Function

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.

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