Clinical trial NCT06080581: Mitochondrial Dysfunctions Driving Insulin Resistance
Official title: Mitochondrial Derangements Driving Muscle Insulin Resistance in Humans
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mitochondrial Myopathies
Mitochondrial Diseases
Mitochondrial Disorders
Keywords: Mitochondrial disease
Muscle metabolism
Insulin resistance
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: University of Copenhagen
First posted: 2023-10-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
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.

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

Detailed description: Background: Peripheral insulin resistance is a major risk factor for metabolic diseases such as type 2 diabetes. Skeletal muscle accounts for the majority of insulin-stimulated glucose disposal, hence restoring insulin action in skeletal muscle is key in the prevention of type 2 diabetes. Mitochondrial dysfunction is implicated in the etiology of muscle insulin resistance. Also, as mitochondrial function is determined by its proteome quantity and quality, alterations in the muscle mitochondrial proteome may play a critical role in the pathophysiology of insulin resistance. However, insulin resistance is multifactorial in nature and whether mitochondrial derangements are a cause or a consequence of impaired insulin action is unclear. In recent years, the study of humans with genetic mutations has shown enormous potential to establish the mechanistic link between two physiological variables; indeed, if the mutation has a functional impact on one of those variables, then the direction of causality can be readily ascribed. Mitochondrial myopathies are genetic disorders of the mitochondrial respiratory chain affecting predominantly skeletal muscle. Mitochondrial myopathies are caused by pathogenic mutations in either nuclear or mitochondrial DNA (mtDNA), which ultimately lead to mitochondrial dysfunction. Although the prevalence of mtDNA mutations is just 1 in 5,000, the study of patients with mtDNA defects has the potential to provide unique information on the pathogenic role of mitochondrial derangements that is disproportionate to the rarity of affected individuals. The m.3243A\>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene is the most common mutation leading to mitochondrial myopathy in humans. The m.3243A\>G mutation is associated with impaired glucose tolerance and insulin resistance in skeletal muscle. Most importantly, insulin resistance precedes impairments of β-cell function in carriers of the m.3243A\>G mutation, making these patients an ideal human model to study the causative nexus between muscle mitochondrial dysfunction and insulin resistance. Thus, a comprehensive characterization of mitochondrial functional defects and the associated proteome alterations in patients harboring a mtDNA mutation associated with an insulin-resistant phenotype may elucidate the causal nexus between mitochondrial derangements and insulin resistance. Also, as mitochondrial dysfunction exhibits many faces (e.g. reduced oxygen consumption rate, impaired ATP synthesis, overproduction of reactive oxygen species, altered membrane potential), such an approach may clarify which features of mitochondrial dysfunction play a prominent role in the pathogenesis of insulin resistance.

Objective: To characterize muscle mitochondrial defects in individuals harboring pathogenic mitochondrial DNA (mtDNA) mutations associated with an insulin-resistant phenotype.

Study design: Case-control study in individuals with pathogenic mtDNA mutations (n=15) and healthy controls (n=15) matched for sex, age, and physical activity level.

Endpoint: Differences between individuals with pathogenic mtDNA mutations and controls.

Eligibility criteria: Eligibility criteria for individuals with pathogenic mtDNA mutations

Inclusion criteria:

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

Exclusion criteria:

* 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

Exclusion criteria:

* 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

Primary outcomes:
measure: Skeletal muscle insulin sensitivity
timeFrame: 90-150 minutes after initiation of the hyperinsulinemic euglycemic clamp
measure: Whole-body insulin sensitivity
timeFrame: 90-150 minutes after initiation of the hyperinsulinemic euglycemic clamp
measure: Muscle mitochondrial respiration
timeFrame: Baseline
measure: Muscle mitochondrial reactive oxygen species (ROS) production
timeFrame: Baseline
measure: Muscle mitochondrial proteome
timeFrame: Baseline
Secondary outcomes:
measure: Glucose tolerance
timeFrame: 0-180 minutes after ingestion of an oral glucose solution
measure: Beta cell function
timeFrame: 0-180 minutes after ingestion of an oral glucose solution
measure: Muscle mtDNA heteroplasmy
timeFrame: Baseline
measure: Muscle insulin signaling
timeFrame: Before (baseline) and 0-150 minutes after initiation of a hyperinsulinemic-euglycemic clamp
measure: Muscle integrated stress response signaling proteins
timeFrame: Baseline
measure: Muscle integrated stress response genes
timeFrame: Baseline
measure: Muscle release of FGF21 and GDF15
timeFrame: Before (baseline) and 0-150 minutes after initiation of a hyperinsulinemic-euglycemic clamp
Other outcomes:
measure: Body composition
timeFrame: Baseline
measure: Leg muscle mass
timeFrame: Baseline
measure: Physical activity level
timeFrame: Baseline
measure: Self-reported physical activity
timeFrame: Baseline
measure: Cardiorespiratory fitness
timeFrame: Baseline
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Matteo Fiorenza, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: John Vissing, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol. 2006 Nov;18(6):636-41. doi: 10.1097/01.bor.0000245729.17759.f2.
citation: 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.
citation: 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.
citation: 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.
citation: 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.