Effect of Dietary Glycemic Index on Beta-cell Function

Not Applicable

Completed

Conditions: Impaired Glucose Tolerance
Oxidative Stress
Prediabetes
Impaired Fasting Glucose

Interventions: Other: low glycemic index (LGI) diet
Drug: high glycemic index diet plus N-acetylcysteine
Other: high glycemic index (HGI) diet plus placebo (PLAC)

Registration Number: NCT01386645

Lead Sponsor: Seattle Institute for Biomedical and Clinical Research

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low GI diet	low glycemic index (LGI) diet	low glycemic index diet
High GI diet NAC	high glycemic index diet plus N-acetylcysteine	high glycemic index diet plus N-acetylcysteine
High GI diet placebo	high glycemic index (HGI) diet plus placebo (PLAC)	high glycemic index diet plus placebo

Primary Outcome Measures

Name	Time	Method
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

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