Mitochondrial Dysfunctions Driving Insulin Resistance

NCT06080581 | Completed

• 1 other identifier: MITO-DYS-IR
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The overarching aim of this observational study is to characterize muscle mitochondrial defects in individuals harboring pathogenic mitochondrial DNA (mtDNA) mutations associated with an insulin-resistant phenotype. In a case-control design, individuals with pathogenic mtDNA mutations will be compared to controls matched for sex, age, and physical activity level. Participants will attend a screening visit and two experimental trials including:

• An oral glucose tolerance test
• A hyperinsulinemic-euglycemic clamp combined with measurements of femoral artery blood flow and arteriovenous difference of glucose
• Muscle biopsy samples

Conditions

Mitochondrial Myopathies; Mitochondrial Diseases; Mitochondrial Disorders

Keywords

Mitochondrial disease; Muscle metabolism; Insulin resistance

Outcome Measures

Primary Outcomes (5)

• Skeletal muscle insulin sensitivity

  Insulin-stimulated muscle glucose uptake is determined by the hyperinsulinemic-euglycemic clamp method integrated with measurements of femoral artery blood flow and arteriovenous difference of glucose

  90-150 minutes after initiation of the hyperinsulinemic euglycemic clamp

• Whole-body insulin sensitivity

  Whole-body insulin sensitivity is determined by the hyperinsulinemic-euglycemic clamp method

  90-150 minutes after initiation of the hyperinsulinemic euglycemic clamp

• Muscle mitochondrial respiration

  Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized fibers from muscle biopsy samples

  Baseline

• Muscle mitochondrial reactive oxygen species (ROS) production

  Mitochondrial H2O2 emission rates are measured by high-resolution fluorometry in permeabilized fibers from muscle biopsy samples

  Baseline

• Muscle mitochondrial proteome

  Mitochondrial proteome signatures are determined by mass spectrometry-based proteomics in muscle biopsy samples

  Baseline

Secondary Outcomes (7)

• Glucose tolerance

  0-180 minutes after ingestion of an oral glucose solution

• Beta cell function

  0-180 minutes after ingestion of an oral glucose solution

• Muscle mtDNA heteroplasmy

  Baseline

• Muscle insulin signaling

  Before (baseline) and 0-150 minutes after initiation of a hyperinsulinemic-euglycemic clamp

• Muscle integrated stress response signaling proteins

  Baseline

Other Outcomes (5)

• Body composition

  Baseline

• Leg muscle mass

  Baseline

• Physical activity level

  Baseline

Study Arms (2)

Mitochondrial myopathy

Individuals with pathogenic mtDNA mutations

Control

Individuals without mtDNA mutations

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals with mitochondrial myopathy due to pathogenic mtDNA mutations are identified and recruited from the Copenhagen Neuromuscular Center or the Department of Clinical Genetics (Rigshospitalet). Control volunteers are recruited via recruitment announcements in Denmark.

You may qualify if:

• Known m.3243A\>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene
• Other known mtDNA point mutations

You may not qualify if:

• Use of antiarrhythmic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
• Diagnosed severe heart disease, dysregulated thyroid gland conditions, or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures.
• Pregnancy
• Eligibility criteria for controls
• Current and regular use of antidiabetic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
• Diagnosed heart disease, symptomatic asthma, liver cirrhosis or -failure, chronic kidney disease, dysregulated thyroid gland conditions or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures
• Daily use of tobacco products
• Excessive alcohol consumption
• Pregnancy

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• University of Copenhagen: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, Denmark, 2100, Denmark

Location

Related Publications (15)

• DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991 Mar;14(3):173-94. doi: 10.2337/diacare.14.3.173.

  PMID: 2044434 BACKGROUND

• DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982 Oct;23(4):313-9. doi: 10.1007/BF00253736.

  PMID: 6754515 BACKGROUND

• DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985 Jul;76(1):149-55. doi: 10.1172/JCI111938.

  PMID: 3894418 BACKGROUND

• Diaz-Vegas A, Sanchez-Aguilera P, Krycer JR, Morales PE, Monsalves-Alvarez M, Cifuentes M, Rothermel BA, Lavandero S. Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocr Rev. 2020 Jun 1;41(3):bnaa005. doi: 10.1210/endrev/bnaa005.

  PMID: 32179913 BACKGROUND

• Hesselink MK, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol. 2016 Nov;12(11):633-645. doi: 10.1038/nrendo.2016.104. Epub 2016 Jul 22.

  PMID: 27448057 BACKGROUND

• Parish R, Petersen KF. Mitochondrial dysfunction and type 2 diabetes. Curr Diab Rep. 2005 Jun;5(3):177-83. doi: 10.1007/s11892-005-0006-3.

  PMID: 15929863 BACKGROUND

• Zabielski P, Lanza IR, Gopala S, Heppelmann CJ, Bergen HR 3rd, Dasari S, Nair KS. Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice. Diabetes. 2016 Mar;65(3):561-73. doi: 10.2337/db15-0823. Epub 2015 Dec 30.

  PMID: 26718503 BACKGROUND

• Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018 Oct 1;98(4):2133-2223. doi: 10.1152/physrev.00063.2017.

  PMID: 30067154 BACKGROUND

• O'Rahilly S. "Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021 Jan;70(1):29-38. doi: 10.2337/dbi19-0037.

  PMID: 33355307 BACKGROUND

• Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 Apr 12;544(7649):235-239. doi: 10.1038/nature22034.

  PMID: 28406212 BACKGROUND

• DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol. 2006 Nov;18(6):636-41. doi: 10.1097/01.bor.0000245729.17759.f2.

  PMID: 17053512 BACKGROUND

• Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015 May;77(5):753-9. doi: 10.1002/ana.24362. Epub 2015 Mar 28.

  PMID: 25652200 BACKGROUND

• Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. 2008 Aug;83(2):254-60. doi: 10.1016/j.ajhg.2008.07.004.

  PMID: 18674747 BACKGROUND

• Frederiksen AL, Jeppesen TD, Vissing J, Schwartz M, Kyvik KO, Schmitz O, Poulsen PL, Andersen PH. High prevalence of impaired glucose homeostasis and myopathy in asymptomatic and oligosymptomatic 3243A>G mitochondrial DNA mutation-positive subjects. J Clin Endocrinol Metab. 2009 Aug;94(8):2872-9. doi: 10.1210/jc.2009-0235. Epub 2009 May 26.

  PMID: 19470628 BACKGROUND

• Lindroos MM, Majamaa K, Tura A, Mari A, Kalliokoski KK, Taittonen MT, Iozzo P, Nuutila P. m.3243A>G mutation in mitochondrial DNA leads to decreased insulin sensitivity in skeletal muscle and to progressive beta-cell dysfunction. Diabetes. 2009 Mar;58(3):543-9. doi: 10.2337/db08-0981. Epub 2008 Dec 10.

  PMID: 19073775 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood, muscle tissue

MeSH Terms

Conditions

Mitochondrial Myopathies; Mitochondrial Diseases; Insulin Resistance

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperinsulinism; Glucose Metabolism Disorders

Study Officials

• Matteo Fiorenza, Ph.D.

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• John Vissing, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 29, 2023
• First Posted: October 12, 2023
• Study Start: October 20, 2023
• Primary Completion: December 20, 2024
• Study Completion: December 20, 2024
• Last Updated: June 22, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)