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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04088981
• Other study ID #: Pro00037991
• Status: Suspended
• Phase: N/A
• Start date: July 2024
• Est. completion date: July 2025

Study information

• Verified date: November 2023
• Source: Physicians Committee for Responsible Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 60
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria are as follows:

1. Men and women with type 2 diabetes treated by diet and/or oral hypoglycemic agents other that sulfonylureas

2. Age =18 years

3. Body mass index 26-40 kg/m2

4. Medications (antidiabetic, antihypertensive, and lipid-lowering) have been stable for the past 3 months

5. HbA1c between 6-10.5% (42-88 mmol/mol)

Exclusion criteria are as follows:

1. Diabetes mellitus, type 1 and/or treatment with insulin or sulfonylureas

2. Metal implants, such as a cardiac pacemaker or an aneurysm clip

3. History of any endocrine condition that would affect body weight, such as thyroid disease, pituitary abnormality, or Cushing's syndrome

4. Smoking during the past six months

5. 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

6. Use of recreational drugs in the past 6 months

7. 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

8. Pregnancy or intention to become pregnant during the study period

9. Unstable medical or psychiatric illness

10. Evidence of an eating disorder

11. Likely to be disruptive in group sessions

12. Already following a low-fat, vegan diet

13. Lack of English fluency

14. Inability to maintain current medication regimen

15. Inability or unwillingness to participate in all components of the study

16. 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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Hypersensitivity
• Insulin Resistance

Intervention

Behavioral:
• Dietary intervention
Low-fat, plant-based diet and a portion-controlled diet

Locations

Country	Name	City	State
United States	Physicians Committee for Responsible Medicine	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Physicians Committee for Responsible Medicine	Yale University

Country where clinical trial is conducted

United States, 

References & Publications (20)

Bachmann OP, Dahl DB, Brechtel K, Machann J, Haap M, Maier T, Loviscach M, Stumvoll M, Claussen CD, Schick F, Haring HU, Jacob S. Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans. Diabetes. 2001 Nov;50(11):2579-84. doi: 10.2337/diabetes.50.11.2579. — View Citation

Bajaj M, Baig R, Suraamornkul S, Hardies LJ, Coletta DK, Cline GW, Monroy A, Koul S, Sriwijitkamol A, Musi N, Shulman GI, DeFronzo RA. Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010 Apr;95(4):1916-23. doi: 10.1210/jc.2009-0911. Epub 2010 Feb 15. — View Citation

Fabris R, Mingrone G, Milan G, Manco M, Granzotto M, Dalla Pozza A, Scarda A, Serra R, Greco AV, Federspil G, Vettor R. Further lowering of muscle lipid oxidative capacity in obese subjects after biliopancreatic diversion. J Clin Endocrinol Metab. 2004 Apr;89(4):1753-9. doi: 10.1210/jc.2003-031343. — View Citation

Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Pettiti M, Natali A, Mari A, DeFronzo RA. Predominant role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance. Diabetologia. 2003 Sep;46(9):1211-9. doi: 10.1007/s00125-003-1169-6. Epub 2003 Jul 23. — View Citation

Goodpaster BH, Theriault R, Watkins SC, Kelley DE. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism. 2000 Apr;49(4):467-72. doi: 10.1016/s0026-0495(00)80010-4. — View Citation

Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M, Vettor R, Camastra S, Ferrannini E. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes. 2002 Jan;51(1):144-51. doi: 10.2337/diabetes.51.1.144. — View Citation

Johansson L, Roos M, Kullberg J, Weis J, Ahlstrom H, Sundbom M, Eden Engstrom B, Karlsson FA. Lipid mobilization following Roux-en-Y gastric bypass examined by magnetic resonance imaging and spectroscopy. Obes Surg. 2008 Oct;18(10):1297-304. doi: 10.1007/s11695-008-9484-0. Epub 2008 Apr 8. — View Citation

Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia. 1999 Jan;42(1):113-6. doi: 10.1007/s001250051123. Erratum In: Diabetologia 1999 Mar;42(3):386. Diabetologia 1999 Oct;42(10):1269. — View Citation

Larson-Meyer DE, Newcomer BR, Ravussin E, Volaufova J, Bennett B, Chalew S, Cefalu WT, Sothern M. Intrahepatic and intramyocellular lipids are determinants of insulin resistance in prepubertal children. Diabetologia. 2011 Apr;54(4):869-75. doi: 10.1007/s00125-010-2022-3. Epub 2010 Dec 23. — View Citation

Machado MV, Ferreira DM, Castro RE, Silvestre AR, Evangelista T, Coutinho J, Carepa F, Costa A, Rodrigues CM, Cortez-Pinto H. Liver and muscle in morbid obesity: the interplay of fatty liver and insulin resistance. PLoS One. 2012;7(2):e31738. doi: 10.1371/journal.pone.0031738. Epub 2012 Feb 16. — View Citation

Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: Pathophysiology, evidence, and practice. Hepatology. 2016 Jun;63(6):2032-43. doi: 10.1002/hep.28392. Epub 2016 Jan 22. — View Citation

Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes. 1999 Aug;48(8):1600-6. doi: 10.2337/diabetes.48.8.1600. — View Citation

Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8236-40. doi: 10.1073/pnas.1205675109. Epub 2012 Apr 30. — View Citation

Phielix E, Brehm A, Bernroider E, Krssak M, Anderwald CH, Krebs M, Schmid AI, Nowotny P, Roden M. Effects of pioglitazone versus glimepiride exposure on hepatocellular fat content in type 2 diabetes. Diabetes Obes Metab. 2013 Oct;15(10):915-22. doi: 10.1111/dom.12112. Epub 2013 May 1. — View Citation

Sanchez-Munoz V, Salas-Romero R, Del Villar-Morales A, Martinez-Coria E, Pegueros-Perez A, Franco-Sanchez JG. [Decrease of liver fat content by aerobic exercise or metformin therapy in overweight or obese women]. Rev Invest Clin. 2013 Jul-Aug;65(4):307-17. Spanish. — View Citation

Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014 Sep 18;371(12):1131-41. doi: 10.1056/NEJMra1011035. No abstract available. Erratum In: N Engl J Med. 2014 Dec 4;371(23):2241. — View Citation

Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma YZ, Savoye M, Rothman DL, Shulman GI, Caprio S. Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes. 2002 Apr;51(4):1022-7. doi: 10.2337/diabetes.51.4.1022. — View Citation

Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes. 2005 Jul;54(7):1926-33. doi: 10.2337/diabetes.54.7.1926. — View Citation

Thamer C, Machann J, Bachmann O, Haap M, Dahl D, Wietek B, Tschritter O, Niess A, Brechtel K, Fritsche A, Claussen C, Jacob S, Schick F, Haring HU, Stumvoll M. Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. J Clin Endocrinol Metab. 2003 Apr;88(4):1785-91. doi: 10.1210/jc.2002-021674. — View Citation

Wang C, Liu F, Yuan Y, Wu J, Wang H, Zhang L, Hu P, Li Z, Li Q, Ye J. Metformin suppresses lipid accumulation in skeletal muscle by promoting fatty acid oxidation. Clin Lab. 2014;60(6):887-96. doi: 10.7754/clin.lab.2013.130531. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Advanced Glycation Endproducts (AGEs)	Advanced Glycation Endproducts (AGEs) will be measured using the AGE Reader mu by Diagnoptics.	1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
Other	Endothelial function	Endothelial function will be measured through use of the itamar EndoPAT, which quantifies the endothelium-mediated changes in vascular tone elicited by a 5-minute occlusion of the brachial artery.	1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Concentration of plasma lipids	Change in plasma cholesterol & triglycerides.	Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
Secondary	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