Back to resultsMuscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY)
Primary Purpose
Diabetes
Status
Completed
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Training or detraining
Sponsored by
About this trial
This is an interventional basic science trial for Diabetes
Eligibility Criteria
Inclusion Criteria:
- Type 2 diabetic patients, aged between 20-65, diagnosed as per WHO criteria, diet controlled or diet and any of the following oral hypoglycemics: metformin, sulphonylureas, glitazones, gliptins, acarbose, but not requiring insulin for controlling of blood glucose.
- Trained, athletic healthy controls, aged 18 and over.
- Participant who is willing and able to give informed consent for participation in the study.
- Able to perform exercise testing.
Exclusion Criteria:
- Any history of known coronary artery disease.
- Other endocrine conditions
- Impaired renal function defined as eGFR<60mls/min/1.73m2
- Known resting/24 hour BP >160/100mmHg
- Participants on ACE inhibitors
- Participants on PPAR agonists
- Participants on omega 3 fatty acids
- The existence of any medical or surgical condition that in the judgement of the investigators may interfere with the exercise regime, FA metabolism or may compromise the safety of the subject
- Presence of other significant concomitant heart diseases such as ischaemic, valvular, pericardial heart disease or cardiomyopathy, skeletal muscle disorders
- Healthy volunteers that are on any chronic medication that in the judgment of the investigators is likely to affect the outcome of the study
- Significant asthma
- Significant pulmonary disease
- Participants unable to cycle on the ergometer
- Unable to perform exercise testing (e.g. prosthetic limbs)
Sites / Locations
- Cardiac Research Office
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Healthy Volunteers
Diabetic Patients
Arm Description
Healthy volunteers will undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy Followed by a period of detraining. They will then undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy
Diabetic patients will undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy They will then undergo a supervised training period. They will then undergo the following: CPEX with/without stable isotope infusion Muscle biopsies Magnetic Resonance Spectroscopy
Outcomes
Primary Outcome Measures
Non-invasive 1H Magnetic Resonance Spectroscopy of vastus lateralis
Assessment of energetics of vastus lateralis by MRS
Secondary Outcome Measures
Saturated and unsaturated lipid pool turnover examined by stable isotopes
Lipid pool turnover as examined by stable isotope infusion
Full Information
NCT ID
NCT03065140
First Posted
December 7, 2016
Last Updated
August 30, 2022
Sponsor
University of Aberdeen
Collaborators
NHS Grampian
1. Study Identification
Unique Protocol Identification Number
NCT03065140
Brief Title
Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity
Acronym
MISTY
Official Title
Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity - the MISTY Study
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
September 2016 (Actual)
Primary Completion Date
January 2019 (Actual)
Study Completion Date
January 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aberdeen
Collaborators
NHS Grampian
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Early research found that high levels of fat within muscle meant poorer control of blood sugar. However, more recent research has shown that athletes have similar levels of fat within muscle, but in contrast, they have very good control of blood sugar. The investigators are not sure why this is and want to find out if the fat within muscle can be changed to improve blood sugar control, as good blood sugar control reduces the risk of heart disease, diabetes and stroke.
Detailed Description
Higher levels of triglycerides (TG) and diacylglycerols (DAG) are found in skeletal muscle of patients with obesity/diabetes as well as in trained athletes. Despite similar metabolic storage, patients and athletes have opposite insulin sensitivity phenotypes and an explanation for this is lacking. The investigators' objective is to understand how these fat compartments can be beneficially modulated to improve insulin resistance and cardio-metabolic risk. The investigators will investigate if either structural differences (saturated versus unsaturated balance of TG and DAG side-chains) or different handling abilities (fast versus slow lipid pool turnover) will be induced by exercise capacity interventions in athletes and in diabetic patients. In a longitudinal study pre- and post-exercise, the investigators will use novel, non-invasive 1H-Magnetic Resonance Spectroscopy to benchmark the saturated/unsaturated compartments against skeletal muscle biopsies for the first time and stable isotope analysis for fat compartments' rate of turnover.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Healthy Volunteers
Arm Type
Experimental
Arm Description
Healthy volunteers will undergo the following:
CPEX with/without stable isotope infusion
Muscle biopsies
Magnetic Resonance Spectroscopy Followed by a period of detraining.
They will then undergo the following:
CPEX with/without stable isotope infusion
Muscle biopsies
Magnetic Resonance Spectroscopy
Arm Title
Diabetic Patients
Arm Type
Experimental
Arm Description
Diabetic patients will undergo the following:
CPEX with/without stable isotope infusion
Muscle biopsies
Magnetic Resonance Spectroscopy They will then undergo a supervised training period.
They will then undergo the following:
CPEX with/without stable isotope infusion
Muscle biopsies
Magnetic Resonance Spectroscopy
Intervention Type
Other
Intervention Name(s)
Training or detraining
Other Intervention Name(s)
Detraining or training
Intervention Description
A period of detraining or a supervised exercise program.
Primary Outcome Measure Information:
Title
Non-invasive 1H Magnetic Resonance Spectroscopy of vastus lateralis
Description
Assessment of energetics of vastus lateralis by MRS
Time Frame
One Hour
Secondary Outcome Measure Information:
Title
Saturated and unsaturated lipid pool turnover examined by stable isotopes
Description
Lipid pool turnover as examined by stable isotope infusion
Time Frame
One hour
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Type 2 diabetic patients, aged between 20-65, diagnosed as per WHO criteria, diet controlled or diet and any of the following oral hypoglycemics: metformin, sulphonylureas, glitazones, gliptins, acarbose, but not requiring insulin for controlling of blood glucose.
Trained, athletic healthy controls, aged 18 and over.
Participant who is willing and able to give informed consent for participation in the study.
Able to perform exercise testing.
Exclusion Criteria:
Any history of known coronary artery disease.
Other endocrine conditions
Impaired renal function defined as eGFR<60mls/min/1.73m2
Known resting/24 hour BP >160/100mmHg
Participants on ACE inhibitors
Participants on PPAR agonists
Participants on omega 3 fatty acids
The existence of any medical or surgical condition that in the judgement of the investigators may interfere with the exercise regime, FA metabolism or may compromise the safety of the subject
Presence of other significant concomitant heart diseases such as ischaemic, valvular, pericardial heart disease or cardiomyopathy, skeletal muscle disorders
Healthy volunteers that are on any chronic medication that in the judgment of the investigators is likely to affect the outcome of the study
Significant asthma
Significant pulmonary disease
Participants unable to cycle on the ergometer
Unable to perform exercise testing (e.g. prosthetic limbs)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dana Dawson, MD
Organizational Affiliation
University of Aberdeen Employee
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cardiac Research Office
City
Aberdeen
State/Province
Aberdeenshire
ZIP/Postal Code
AB25 2ZN
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
23752495
Citation
Lobley GE, Holtrop G, Bremner DM, Calder AG, Milne E, Johnstone AM. Impact of short term consumption of diets high in either non-starch polysaccharides or resistant starch in comparison with moderate weight loss on indices of insulin sensitivity in subjects with metabolic syndrome. Nutrients. 2013 Jun 10;5(6):2144-72. doi: 10.3390/nu5062144.
Results Reference
background
PubMed Identifier
19141688
Citation
Wilson FA, van den Borne JJ, Calder AG, O'Kennedy N, Holtrop G, Rees WD, Lobley GE. Tissue methionine cycle activity and homocysteine metabolism in female rats: impact of dietary methionine and folate plus choline. Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E702-13. doi: 10.1152/ajpendo.90670.2008. Epub 2009 Jan 13.
Results Reference
background
PubMed Identifier
8769349
Citation
Phillips DI, Caddy S, Ilic V, Fielding BA, Frayn KN, Borthwick AC, Taylor R. Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. Metabolism. 1996 Aug;45(8):947-50. doi: 10.1016/s0026-0495(96)90260-7.
Results Reference
background
PubMed Identifier
21930939
Citation
Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16381-5. doi: 10.1073/pnas.1113359108. Epub 2011 Sep 19.
Results Reference
background
PubMed Identifier
11739435
Citation
Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001 Dec;86(12):5755-61. doi: 10.1210/jcem.86.12.8075.
Results Reference
background
PubMed Identifier
21873552
Citation
Amati F, Dube JJ, Alvarez-Carnero E, Edreira MM, Chomentowski P, Coen PM, Switzer GE, Bickel PE, Stefanovic-Racic M, Toledo FG, Goodpaster BH. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes. 2011 Oct;60(10):2588-97. doi: 10.2337/db10-1221. Epub 2011 Aug 26.
Results Reference
background
PubMed Identifier
10690948
Citation
Manco M, Mingrone G, Greco AV, Capristo E, Gniuli D, De Gaetano A, Gasbarrini G. Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides. Metabolism. 2000 Feb;49(2):220-4. doi: 10.1016/s0026-0495(00)91377-5.
Results Reference
background
PubMed Identifier
19615699
Citation
Anastasiou CA, Kavouras SA, Lentzas Y, Gova A, Sidossis LS, Melidonis A. Diabetes mellitus is associated with increased intramyocellular triglyceride, but not diglyceride, content in obese humans. Metabolism. 2009 Nov;58(11):1636-42. doi: 10.1016/j.metabol.2009.05.019. Epub 2009 Jul 16.
Results Reference
background
PubMed Identifier
19833891
Citation
Coen PM, Dube JJ, Amati F, Stefanovic-Racic M, Ferrell RE, Toledo FG, Goodpaster BH. Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes. 2010 Jan;59(1):80-8. doi: 10.2337/db09-0988. Epub 2009 Oct 15.
Results Reference
background
PubMed Identifier
20299618
Citation
Bergman BC, Perreault L, Hunerdosse DM, Koehler MC, Samek AM, Eckel RH. Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes. J Appl Physiol (1985). 2010 May;108(5):1134-41. doi: 10.1152/japplphysiol.00684.2009. Epub 2010 Mar 18.
Results Reference
background
PubMed Identifier
3292505
Citation
King DS, Dalsky GP, Clutter WE, Young DA, Staten MA, Cryer PE, Holloszy JO. Effects of exercise and lack of exercise on insulin sensitivity and responsiveness. J Appl Physiol (1985). 1988 May;64(5):1942-6. doi: 10.1152/jappl.1988.64.5.1942.
Results Reference
background
PubMed Identifier
21327867
Citation
Dube JJ, Amati F, Toledo FG, Stefanovic-Racic M, Rossi A, Coen P, Goodpaster BH. Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia. 2011 May;54(5):1147-56. doi: 10.1007/s00125-011-2065-0. Epub 2011 Feb 17.
Results Reference
background
PubMed Identifier
18319352
Citation
Dube JJ, Amati F, Stefanovic-Racic M, Toledo FG, Sauers SE, Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. Am J Physiol Endocrinol Metab. 2008 May;294(5):E882-8. doi: 10.1152/ajpendo.00769.2007. Epub 2008 Mar 4.
Results Reference
background
PubMed Identifier
12941756
Citation
Goodpaster BH, Katsiaras A, Kelley DE. Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity. Diabetes. 2003 Sep;52(9):2191-7. doi: 10.2337/diabetes.52.9.2191.
Results Reference
background
PubMed Identifier
15734832
Citation
Summers SA, Nelson DH. A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing's syndrome. Diabetes. 2005 Mar;54(3):591-602. doi: 10.2337/diabetes.54.3.591.
Results Reference
background
PubMed Identifier
16464906
Citation
Bruce CR, Thrush AB, Mertz VA, Bezaire V, Chabowski A, Heigenhauser GJ, Dyck DJ. Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E99-E107. doi: 10.1152/ajpendo.00587.2005. Epub 2006 Feb 7.
Results Reference
background
PubMed Identifier
11294494
Citation
Brechtel K, Niess AM, Machann J, Rett K, Schick F, Claussen CD, Dickhuth HH, Haering HU, Jacob S. Utilisation of intramyocellular lipids (IMCLs) during exercise as assessed by proton magnetic resonance spectroscopy (1H-MRS). Horm Metab Res. 2001 Feb;33(2):63-6. doi: 10.1055/s-2001-12407.
Results Reference
background
PubMed Identifier
11423483
Citation
Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001 Jul;50(7):1612-7. doi: 10.2337/diabetes.50.7.1612.
Results Reference
background
PubMed Identifier
21213017
Citation
Machann J, Etzel M, Thamer C, Haring HU, Claussen CD, Fritsche A, Schick F. Morning to evening changes of intramyocellular lipid content in dependence on nutrition and physical activity during one single day: a volume selective 1H-MRS study. MAGMA. 2011 Feb;24(1):29-33. doi: 10.1007/s10334-010-0233-8. Epub 2011 Jan 7.
Results Reference
background
PubMed Identifier
10600804
Citation
Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol. 1999 Dec;277(6):E1130-41. doi: 10.1152/ajpendo.1999.277.6.E1130.
Results Reference
background
PubMed Identifier
20035285
Citation
Perreault L, Bergman BC, Hunerdosse DM, Playdon MC, Eckel RH. Inflexibility in intramuscular triglyceride fractional synthesis distinguishes prediabetes from obesity in humans. Obesity (Silver Spring). 2010 Aug;18(8):1524-31. doi: 10.1038/oby.2009.454. Epub 2009 Dec 24.
Results Reference
background
PubMed Identifier
11937037
Citation
Lizcano JM, Alessi DR. The insulin signalling pathway. Curr Biol. 2002 Apr 2;12(7):R236-8. doi: 10.1016/s0960-9822(02)00777-7. No abstract available.
Results Reference
background
PubMed Identifier
17724080
Citation
Delibegovic M, Bence KK, Mody N, Hong EG, Ko HJ, Kim JK, Kahn BB, Neel BG. Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. Mol Cell Biol. 2007 Nov;27(21):7727-34. doi: 10.1128/MCB.00959-07. Epub 2007 Aug 27.
Results Reference
background
PubMed Identifier
16845389
Citation
Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006 Aug;12(8):917-24. doi: 10.1038/nm1435. Epub 2006 Jul 16. Erratum In: Nat Med. 2010 Feb;16(2):237.
Results Reference
background
PubMed Identifier
17075965
Citation
Boesch C, Machann J, Vermathen P, Schick F. Role of proton MR for the study of muscle lipid metabolism. NMR Biomed. 2006 Nov;19(7):968-88. doi: 10.1002/nbm.1096.
Results Reference
background
PubMed Identifier
23065738
Citation
Hock A, Fuchs A, Boesiger P, Kollias SS, Henning A. Electrocardiogram-triggered, higher order, projection-based B(0) shimming allows for fast and reproducible shim convergence in spinal cord (1)H MRS. NMR Biomed. 2013 Mar;26(3):329-35. doi: 10.1002/nbm.2852. Epub 2012 Oct 13.
Results Reference
background
PubMed Identifier
22745036
Citation
Hock A, MacMillan EL, Fuchs A, Kreis R, Boesiger P, Kollias SS, Henning A. Non-water-suppressed proton MR spectroscopy improves spectral quality in the human spinal cord. Magn Reson Med. 2013 May;69(5):1253-60. doi: 10.1002/mrm.24387. Epub 2012 Jun 28.
Results Reference
background
PubMed Identifier
12502504
Citation
Kuhlmann J, Neumann-Haefelin C, Belz U, Kalisch J, Juretschke HP, Stein M, Kleinschmidt E, Kramer W, Herling AW. Intramyocellular lipid and insulin resistance: a longitudinal in vivo 1H-spectroscopic study in Zucker diabetic fatty rats. Diabetes. 2003 Jan;52(1):138-44. doi: 10.2337/diabetes.52.1.138.
Results Reference
background
PubMed Identifier
22441585
Citation
Ye Q, Danzer CF, Fuchs A, Wolfrum C, Rudin M. Hepatic lipid composition differs between ob/ob and ob/+ control mice as determined by using in vivo localized proton magnetic resonance spectroscopy. MAGMA. 2012 Oct;25(5):381-9. doi: 10.1007/s10334-012-0310-2. Epub 2012 Mar 23.
Results Reference
background
PubMed Identifier
15165998
Citation
van Loon LJ, Koopman R, Manders R, van der Weegen W, van Kranenburg GP, Keizer HA. Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes. Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E558-65. doi: 10.1152/ajpendo.00464.2003. Epub 2004 May 27.
Results Reference
background
PubMed Identifier
23837031
Citation
Liu Y, Li J, Zhang Z, Tang Y, Chen Z, Wang Z. Effects of exercise intervention on vascular endothelium functions of patients with impaired glucose tolerance during prediabetes mellitus. Exp Ther Med. 2013 Jun;5(6):1559-1565. doi: 10.3892/etm.2013.1064. Epub 2013 Apr 11.
Results Reference
background
PubMed Identifier
23234409
Citation
Dudzinska W, Lubkowska A, Jakubowska K, Suska M, Skotnicka E. Insulin resistance induced by maximal exercise correlates with a post-exercise increase in uridine concentration in the blood of healthy young men. Physiol Res. 2013;62(2):163-70. doi: 10.33549/physiolres.932355. Epub 2012 Dec 13. Erratum In: Physiol Res. 2013 Jul 18;62(3):337.
Results Reference
background
PubMed Identifier
20739510
Citation
Alibegovic AC, Sonne MP, Hojbjerre L, Bork-Jensen J, Jacobsen S, Nilsson E, Faerch K, Hiscock N, Mortensen B, Friedrichsen M, Stallknecht B, Dela F, Vaag A. Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab. 2010 Nov;299(5):E752-63. doi: 10.1152/ajpendo.00590.2009. Epub 2010 Aug 24.
Results Reference
background
PubMed Identifier
22318952
Citation
Ducommun S, Wang HY, Sakamoto K, MacKintosh C, Chen S. Thr649Ala-AS160 knock-in mutation does not impair contraction/AICAR-induced glucose transport in mouse muscle. Am J Physiol Endocrinol Metab. 2012 May 15;302(9):E1036-43. doi: 10.1152/ajpendo.00379.2011. Epub 2012 Feb 7.
Results Reference
background
Citation
ECG-Triggered and Respiratory Gated Image Based B0 Shimming for Single Voxel Spectroscopy of the Myocardium at 3T. 21st Annual Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM 2013), Salt Lake City, UT, USA. 2013
Results Reference
background
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Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity
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