Effect of Ketogenic Diet on Glucose Metabolism and Energy Expenditure in Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The study team will examine the effect of a ketogenic diet alone and ketogenic diet supplemented with oral ketones on how the body of individuals with type 2 diabetes respond to insulin, regulates insulin secretion, food intake and energetic pathways and influences body fat distribution.

Detailed Description
-----------------
Subjects will be randomized into three groups (1) standard, weight maintaining diet containing approximately 25-35% protein, 45-55% carbohydrate, 20-30% fat; (2) weight maintaining isocaloric ketogenic diet containing approximately 15-25% protein, 5-10% carbohydrate, 70-80% fat; (3) weight maintaining isocaloric diet containing approximately 15-25% protein, 5-10% carbohydrate, 70-80% fat supplemented with the ketone ester of beta-hydroxy butyrate, 8 grams every 8 hours to further increase the plasma ketone concentration by  3 mM. Subjects will be further randomized on the basis of: (i) HbA1c 7.0-8.5% and 8.5-10.5% to ensure similar baseline levels of glucose control and (ii) drug naïve versus drug-treated. At the time of screening, after a 10-12 hour overnight fast, indirect calorimetry will be performed with a ventilated hood system for 60 minutes to measure baseline energy expenditure. An initial weight maintenance energy requirement estimate as 1.5 times resting energy expenditure (obtained by indirect calorimetry) will be started. Diets will consist of a 10-day rotating menu using NutriAdmin for meal planning and Nutrition Maker for analysis of recipes Food will be prepared in the Cafeteria and or the Metabolic Kitchen at the Texas Diabetes Institute and certified by a dietician. Subjects will report to the diet kitchen at 8 AM on Monday through Saturday where they will eat their breakfast and pick up food for their lunch and dinner. On Saturday, participants also will be given food for their Sunday meals. Subjects will maintain a daily dietary log with all food consumed. On each visit subjects will be weighed; dietary log will be reviewed and the caloric content of the diet will be adjusted to maintain the body weight constant. Blood pressure will be measured in the reclining position x 2 separate days. Antidiabetic medications will not be changed during the study unless hypoglycemia (fasting plasma glucose <70 mg/dl or symptoms) occurs. The study duration will be 10 days which should be sufficient to observe the effect of hyperketonemia on glucose/lipid metabolism and energy expenditure. If participant cannot come on the last days of his/her diet treatment, than we will extend this period up to 13 days and participant will be given diet for additional days till completion of the study visits.

Official Title
-----------------
Effect of Ketogenic Diet on Glucose Metabolism and Energy Expenditure in Type 2 Diabetes CTMS 20-0042

Conditions
-----------------
Glucose Metabolism Disorders (Including Diabetes Mellitus), Energy Supply; Deficiency, Type 2 Diabetes

Intervention / Treatment
-----------------
* Other: Standard weight maintaining diet
* Other: Weight maintaining isocaloric ketogenic diet
* Dietary Supplement: Beta-hydroxy butyrate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age from 18-70 years BMI = 27.5-42 kg.m2 HbA1c = 7.0-10.5 Weight stable (±4-5lb) in the preceding 3 months Good general health Exclusion Criteria: Use of medications that affect glucose tolerance other than metformin/sulfonylurea/DPP4 Inhibitor Major organ disease Estimated Glomerular filtration rate (eGFR) <60 ml/min Type 1 diabetes Hematocrit < 34 (if HbA1c is in the 8.5 to 10% range)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized into 3 groups. Each group will be assigned to one of 4 arms.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Weight Maintenance<br>Standard weight maintenance diet will be provided for 10 days for subjects who are not currently treated with a T2DM medication. | Other: Standard weight maintaining diet<br>* Diet containing diet approximately 25-35% protein, 45-55% carbohydrate, 20- 30% fat<br>|
| Active Comparator: Isocaloric Diet<br>Isocaloric diet will be provided for 10 days for subjects who are currently treated with a T2DM medication included in the inclusion criteria | Other: Weight maintaining isocaloric ketogenic diet<br>* Isocaloric ketogenic diet containing approximately 15-25% protein, 5-10% carbohydrate,70- 80% fat<br>|
| Active Comparator: Isocaloric Diet with Beta-hydroxy butyrate<br>Isocaloric diet with Beta-hydroxy butyrate will be provided for 10 days for subjects who are not currently treated with a T2DM medication. | Other: Weight maintaining isocaloric ketogenic diet<br>* Isocaloric ketogenic diet containing approximately 15-25% protein, 5-10% carbohydrate,70- 80% fat<br>Dietary Supplement: Beta-hydroxy butyrate<br>* A supplement of ketone ester of beta-hydroxy butyrate<br>* Other names: BHOB;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting plasma glucose (FPG) | A change in FPG will be measured | Baseline to 10 days | 
| Hepatic Glucose production (HGP) | Change of hepatic glucose production will be measured using 3H-glucose infusion | Baseline to 10 days | 
| Whole Body Fat Oxidation | Change in whole body fat oxidation will be measured using indirect calorimetry | Baseline to 10 days | 
| Total Body Fat | Change in whole body fat | Baseline to 10 days | 
| Hepatic Fat Content | Change in hepatic fat content | Baseline to 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Insulin | Change in plasma insulin will be measured | Baseline to 10 days | 
| C-peptide | Change in C-peptide will be measured | Baseline to 10 days | 
| Free Fatty Acid (FFA) | Change in FFA will be measured | Baseline to 10 days | 
| Glycerol level | Change in Glycerol level will be measured | Baseline to 10 days | 
| Low density lipoproteins (LDL) | Change in LDL | Baseline to 10 days | 
| High density lipoproteins (HDL) | Change in HDL | Baseline to 10 days | 
| Triglycerides | Change in triglyceride levels | Baseline to 10 days | 
| Urine Microalbumin excretion | Change in urine microalbumin excretion | Baseline to 10 days | 
| Glycated hemoglobin test (HbA1c) | Change in HbA1c | Baseline to 10 days | 
| Fructosamine level | Change in fructosamine | Baseline to 10 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ketogenic diet, Body fat, Insulin secretion