Mitochondrial Dysfunctions Driving Insulin Resistance

Last updated: January 30, 2025
Sponsor: Rigshospitalet, Denmark
Overall Status: Active - Recruiting

Phase

N/A

Condition

Hormone Deficiencies

Diabetes Prevention

Diabetes (Pediatric)

Treatment

N/A

Clinical Study ID

NCT06080581
MITO-DYS-IR
  • Ages > 18
  • All Genders
  • Accepts Healthy Volunteers

Study 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

Eligibility Criteria

Inclusion

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 1gene

  • Other known mtDNA point mutations

Exclusion

Exclusion criteria:

  • Use of antiarrhythmic medications or other medications which, in the opinion of theinvestigators, have the potential to affect outcome measures.

  • Diagnosed severe heart disease, dysregulated thyroid gland conditions, or otherdysregulated endocrinopathies, or other conditions which, in the opinion of theinvestigators, 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, inthe opinion of the investigators, have the potential to affect outcome measures.

  • Diagnosed heart disease, symptomatic asthma, liver cirrhosis or -failure, chronickidney disease, dysregulated thyroid gland conditions or other dysregulatedendocrinopathies, 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

Study Design

Total Participants: 30
Study Start date:
October 20, 2023
Estimated Completion Date:
December 31, 2025

Study 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.

Connect with a study center

  • Rigshospitalet

    Copenhagen, 2100
    Denmark

    Active - Recruiting

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