Clinical trial NCT04088981: Effect of a Dietary Intervention on Intracellular Lipid Levels, Insulin Sensitivity, and Glycemic Control in Type 2 Diabetes
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
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Keywords: insulin sensitivity
glycemic control
intramyocellular
nutrition
hepatocellular
Lead sponsor: Physicians Committee for Responsible Medicine
Sponsor class: OTHER
Collaborators: name: Yale University
First posted: 2019-09-13
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: randomized, cross-over
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Intramyocellular lipid content
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
measure: Hepatocellular lipid content
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
measure: Insulin sensitivity
timeFrame: Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
measure: Concentration of glucose
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
measure: Concentration of C-peptide
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
measure: Rate of glycemic control
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
Secondary outcomes:
measure: Resting energy expenditure
timeFrame: Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
measure: Postprandial metabolism
timeFrame: Change from Baseline to 22 weeks and change from 22 weeks to 44 weeks
measure: Body Composition
timeFrame: Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
measure: Gut microbiome composition
timeFrame: Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
measure: Concentration of plasma lipids
timeFrame: Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
measure: Body weight
timeFrame: Change from baseline to 22 weeks and change from 22 weeks to 44 weeks
Other outcomes:
measure: Advanced Glycation Endproducts (AGEs)
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
measure: Endothelial function
timeFrame: 1.) Change from week 0 to week 22; 2.) Change from week 22 to week 44
Locations:
city: Washington
country: United States
facility: Physicians Committee for Responsible Medicine
state: District of Columbia
Study officials:
affiliation: Physicians Committee for Responsible Medicine
name: Hana Kahleova, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
citation: 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.
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.
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.