Effect of a Dietary Intervention on Intracellular Lipid Levels, Insulin Sensitivity, and Glycemic Control in Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to compare the effects of a low-fat, plant-based dietary intervention and a portion-controlled dietary intervention (compliant with current American Diabetes Association (ADA) guidelines) on changes in intramyocellular and hepatocellular lipid content in adults with type 2 diabetes. Changes in insulin sensitivity and glycemic control will also be assessed in this study. The study duration is 44 weeks.

Detailed Description
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Type 2 diabetes is a disease characterized by discordance between the amount of insulin produced by pancreatic β-cells and the amount of insulin required to overcome insulin resistance in the liver and peripheral tissues. The development of insulin resistance has been strongly associated with the prolonged accumulation of lipids (fats) in the liver cells (hepatocellular lipid) and muscle cells (intramyocellular lipid). Conventional pharmacologic therapeutics for type 2 diabetes, like metformin, are designed to reduce the accumulation of hepatocellular and intramyocellular lipids and, thereby, augment insulin sensitivity. Research has shown that a low-fat, plant-based diet, in which the consumption of lipids is limited, is a similarly effective therapeutic intervention for the reduction of hepatocellular and intramyocellular lipid content and the improvement of insulin sensitivity in type 2 diabetes. The purpose of this study is to compare the effects of low-fat, plant-based dietary intervention and a portion-controlled dietary intervention (compliant with current American Diabetes Association (ADA) guidelines) on hepatocellular and intramyocellular lipid content in adults with type 2 diabetes. Using a cross-over design, participants with type 2 diabetes will be randomly assigned to start with a plant-based or a portion-controlled diet for 22 weeks. The two groups will then switch to the opposite diet regimen for an additional 22 weeks. Before and after each intervention period, the investigators will measure intramuscular and liver fat content. The investigators will also assess the relationship between these variables, insulin sensitivity, and glycemic control. The investigators hypothesize that both dietary interventions will result in reductions in intramuscular and liver fat content, and that these changes will be associated with improvements in insulin sensitivity and glycemic control in individuals with type 2 diabetes. The investigators further hypothesize that the low-fat, plant-based dietary intervention will elicit greater changes in intracellular lipid concentration, compared with the portion-controlled dietary intervention.

Official Title
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Physicians Committee for Responsible Medicine, A Randomized, Crossover Trial of the Effect of a Dietary Intervention on Intracellular Lipid, Insulin Sensitivity, and Glycemic Control in Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Behavioral: Dietary intervention


Participation Criteria
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Eligibility Criteria
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Inclusion criteria are as follows: Men and women with type 2 diabetes treated by diet and/or oral hypoglycemic agents other that sulfonylureas Age ≥18 years Body mass index 26-40 kg/m2 Medications (antidiabetic, antihypertensive, and lipid-lowering) have been stable for the past 3 months HbA1c between 6-10.5% (42-88 mmol/mol) Exclusion criteria are as follows: Diabetes mellitus, type 1 and/or treatment with insulin or sulfonylureas Metal implants, such as a cardiac pacemaker or an aneurysm clip History of any endocrine condition that would affect body weight, such as thyroid disease, pituitary abnormality, or Cushing's syndrome Smoking during the past six months Alcohol consumption of more than 2 drinks per day or the equivalent, episodic increased drinking (e.g., more than 2 drinks per day on weekends), or a history of alcohol abuse or dependency followed by any current use Use of recreational drugs in the past 6 months Use within the preceding six months of medications that affect appetite or body weight, such as estrogens or other hormones, thyroid medications, systemic steroids, antidepressants (tricyclics, MAOIs, SSRIs), antipsychotics, lithium, anticonvulsants, appetite suppressants or other weight-loss drugs, herbs for weight loss or mood, St. John's wort, ephedra, beta blockers Pregnancy or intention to become pregnant during the study period Unstable medical or psychiatric illness Evidence of an eating disorder Likely to be disruptive in group sessions Already following a low-fat, vegan diet Lack of English fluency Inability to maintain current medication regimen Inability or unwillingness to participate in all components of the study Intention to follow another weight-loss method during the trial Participants will also review and complete the Yale MRI Safety Questionnaire to determine eligibility for the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: randomized, cross-over
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low-fat, vegan diet<br>For a 22-week period, participants will be asked to follow a low-fat vegan diet which consists of whole grains, vegetables, legumes, and fruits, with no restriction on energy intake. Animal products and added oils will be excluded. In choosing grain products and starchy vegetables (e.g., bread, potatoes), participants will be encouraged to select those retaining their natural fiber and having a glycemic index <70, using tables standardized to a value of 100 for glucose. | Behavioral: Dietary intervention<br>* Low-fat, plant-based diet and a portion-controlled diet<br>|
| Active Comparator: Portion-controlled diet<br>For a 22-week period, participants will be asked to follow a portion-controlled diet which will include individualized diet plans that reduce daily energy intake by 500 kcal for overweight participants, and keep carbohydrate intake reasonably stable over time. It will derive 50% of total energy from carbohydrates, 20% from protein, and less than 30% from fat (≤7% saturated fat), with less than 200 mg/day of cholesterol/day. | Behavioral: Dietary intervention<br>* Low-fat, plant-based diet and a portion-controlled diet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intramyocellular lipid content | Proton magnetic resonance (MR) spectroscopy at 4T (Bruker) will be implemented to quantify intramyocellular lipid concentrations. | 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44 | 
| Hepatocellular lipid content | Proton magnetic resonance (MR) spectroscopy at 4T (Bruker) will be implemented to quantify intramyocellular lipid concentrations. | 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44 | 
| Insulin sensitivity | Insulin resistance will be assessed by the Homeostatic Model Assessment (HOMA) PREDIM indexes | Change from baseline to 22 weeks and change from 22 weeks to 44 weeks | 
| Concentration of glucose | Concentration of glucose will be assessed during a standard meal test (Boost Plus, Nestle, Vevey, Switzerland; 720 kcal, 34% of energy from fat, 16% protein, 50% carbohydrate). Plasma concentrations of glucose will be measured at 0, 30, 60, 120, and 180 min. | 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44 | 
| Concentration of C-peptide | Concentration of C-peptide be assessed during a standard meal test (Boost Plus, Nestle, Vevey, Switzerland; 720 kcal, 34% of energy from fat, 16% protein, 50% carbohydrate). Concentration of C-peptide will be measured at 0, 30, 60, 120, and 180 min. | 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44 | 
| Rate of glycemic control | Rate of glycemic control will be assessed through HbA1C. | 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting energy expenditure | Resting energy expenditure REE (pulse, respiratory rate and body temperature) will be measured for 20 minutes through indirect calorimetry utilizing a ventilated hood system in fasting participants. | Change from baseline to 22 weeks and change from 22 weeks to 44 weeks | 
| Postprandial metabolism | Postprandial metabolism will be measured by indirect calorimetry. Participants will be asked to report to the laboratory within 60 minutes of waking and after a 12-hour fast. Following 30 minutes of quiet rest in a dimly lit room, pulse, respiratory rate, and body temperature will be measured. Resting energy expenditure will be measured for 20 minutes through indirect calorimetry utilizing a ventilated hood system. Postprandial metabolism will be measured four times, 20 minutes each time, over the course of 3 hours after the standard breakfast. | Change from Baseline to 22 weeks and change from 22 weeks to 44 weeks | 
| Body Composition | Body composition will be measured by dual energy x-ray absorptiometry (Lunar iDXA, GE Healthcare; Madison WI), assessing visceral adipose tissue volume and mass. | Change from baseline to 22 weeks and change from 22 weeks to 44 weeks | 
| Gut microbiome composition | Quantitative determination of microorganisms and global analysis of microbial diversity from stool sample. The mean of the change between time points in bacteria counts. | Change from baseline to 22 weeks and change from 22 weeks to 44 weeks | 
| Concentration of plasma lipids | Change in plasma cholesterol & triglycerides. | Change from baseline to 22 weeks and change from 22 weeks to 44 weeks | 
| Body weight | Change in body weight measured on a calibrated scale. | Change from baseline to 22 weeks and change from 22 weeks to 44 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insulin sensitivity, glycemic control, intramyocellular, nutrition, hepatocellular