Nicotinamide Riboside and Mitochondrial Metabolism

NCT03951285 | Completed

• 1 other identifier: NRtwins_0001
• Study Type: interventional
• Target: 56
• Locations: 0 countries
• Sites: N/A

Brief Summary

Vitamin B3 has recently been found to be a potent modifier of energy metabolism, especially the function of mitochondria. Mitochondria power up all cells in our bodies, by generating fuel, ATP, for cellular functions. In previous studies, it has been discovered that mitochondrial biogenesis and oxidative metabolism in adipose tissue is severely impaired in obesity, already at a young adult age. Here the investigators describe a proposal where they use nicotinamide riboside (NR), a form of vitamin B3 naturally found in milk, to activate dysfunctional mitochondria, in particular the SIRT/NAD+ pathway, and to rescue signs of obesity-related diseases. The investigators use a unique human study design: monozygotic twins either discordant or concordant for obesity, to examine the effects of NR on mitochondrial function in muscle, adipose tissue and the metabolism of the whole body. The upcoming upcoming results are important for understanding the links between mitochondrial dysfunction and chronic metabolic diseases in humans, as well as for clarifying mechanisms of the novel nutritional therapeutic approaches.

Conditions

Obesity

Keywords

Obesity; Metabolic syndrome; Vitamin B3; Nicotinamide riboside; Mitochondrial dysfunction; Mitochondria; Adipose tissue; Skeletal muscle

Outcome Measures

Primary Outcomes (3)

• Mitochondrial biogenesis - mitochondrial DNA quantification

  Change in amount of mitochondrial DNA in skeletal muscle and adipose tissue (mtDNA quantification)

  At baseline and 5 months after supplementation

• Mitochondrial biogenesis - mitochondria-related mRNA expression

  Change in mitochondria-related mRNA expression in skeletal muscle and adipose tissue (qPCR)

  At baseline and 5 months after supplementation

• Mitochondrial biogenesis - electron microscopy

  Change in mitochondria histology by electron microscopy evaluation of skeletal muscle

  At baseline and 5 months after supplementation

Secondary Outcomes (2)

• NAD+ and related metabolite levels in blood

  At baseline and 5 months after supplementation

• Skeletal muscle mitochondrial oxidative capacity

  At baseline and 5 months after supplementation

Other Outcomes (4)

• Body weight and body composition

  At baseline and 5 months after supplementation

• Ectopic lipid accumulation in liver and muscle (in vivo)

  At baseline and 5 months after supplementation

• Whole body insulin sensitivity

  At baseline and 5 months after supplementation

Study Arms (2)

NR

EXPERIMENTAL

One intervention includes healthy BMI-discordant monozygotic twin pairs, which both are treated with NR. With this unique model, the investigators obtain the information on how beneficial NR is in two different BMI classes (obese and leaner) with an identical genomic background. The final dose for NR will be 1 g/day. The daily NR dose is gradually escalated by 250 mg/week so that the full dose of 1 g/day is reached in one month. The intervention time with the full NR dose is 4 months, total intervention time 5 months. At the end of the study, the daily dose will be decreased by 250 mg/week rate.

Dietary Supplement: NR in BMI-discordant twins; Dietary Supplement: NR in BMI-concordant twins

Placebo

PLACEBO COMPARATOR

The second intervention includes monozygotic twins concordant for body weight. It's randomized which member of the twin pair is treated with NR while the other co-twin gets placebo. The final dose for placebo will be 1 g/day. The daily placebo dose is gradually escalated by 250 mg/week so that the full dose of 1 g/day is reached in one month. The intervention time with the full placebo dose is 4 months, total intervention time 5 months. At the end of the study, the daily dose will be decreased by 250 mg/week rate.

Dietary Supplement: NR in BMI-concordant twins

Interventions

NR in BMI-discordant twins DIETARY_SUPPLEMENT

Water-soluble form of vitamin B3, nicotinamide riboside (NR) is used in this study. The NR product name is Niagen, produced by ChromaDex. NR does not cause the known side effects (vasodilation and flushing) of another vitamin B3, niacin.

Also known as: Niagen, Nicotinamide riboside

NR

NR in BMI-concordant twins DIETARY_SUPPLEMENT

Water-soluble form of vitamin B3, nicotinamide riboside (NR) is used in this study. The NR product name is Niagen, produced by ChromaDex. NR does not cause the known side effects (vasodilation and flushing) of another vitamin B3, niacin.

Also known as: Niagen

NR; Placebo

Eligibility Criteria

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

You may qualify if:

• BMI \>18.5 kg/m2 in both members of the twin pair
• Agreed to maintain current level of physical activity throughout the study
• Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 14 days prior to the enrolment and during the study
• Written, informed consent to participate in the study

You may not qualify if:

• Unstable medical conditions as determined by the principal investigator
• Clinically significant abnormal lab results at screening (e.g. AST and/or ALT \> 2 x ULN, and/or bilirubin \> 2 x ULN)
• Subjects who have a planned surgery during the course of the trial
• History of or a current diagnosis of any cancer (except for successfully treated basal cell carcinoma diagnosed less than 5 years prior to screening). Subjects with cancer in full remission more than 5 years after diagnosis are acceptable.
• History of blood/bleeding disorders
• Immunocompromised individuals such as subjects that had undergone organ transplantation or subjects diagnosed with human immunodeficiency virus (HIV)
• Hepatitis
• Blood donation in the previous 2 months
• Anemia (hemoglobin \<120)
• Participation in a clinical research trial within 30 days prior to randomization
• Allergy or sensitivity to study supplement ingredients
• Individuals who are cognitively impaired and/or who are unable to give informed consent.
• Any other condition, which in the principal investigator's opinion may adversely affect the subject's ability to complete the study or its measures or which may have posed significant risk to the subject.

Sponsors & Collaborators

• Helsinki University Central Hospital: lead
• University of Helsinki: collaborator
• University of Iowa: collaborator
• Finnish Institute for Health and Welfare: collaborator
• Göteborg University: collaborator

Related Publications (6)

• Naukkarinen J, Heinonen S, Hakkarainen A, Lundbom J, Vuolteenaho K, Saarinen L, Hautaniemi S, Rodriguez A, Fruhbeck G, Pajunen P, Hyotylainen T, Oresic M, Moilanen E, Suomalainen A, Lundbom N, Kaprio J, Rissanen A, Pietilainen KH. Characterising metabolically healthy obesity in weight-discordant monozygotic twins. Diabetologia. 2014 Jan;57(1):167-76. doi: 10.1007/s00125-013-3066-y. Epub 2013 Oct 8.

  PMID: 24100782 BACKGROUND

• Jukarainen S, Heinonen S, Ramo JT, Rinnankoski-Tuikka R, Rappou E, Tummers M, Muniandy M, Hakkarainen A, Lundbom J, Lundbom N, Kaprio J, Rissanen A, Pirinen E, Pietilainen KH. Obesity Is Associated With Low NAD(+)/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins. J Clin Endocrinol Metab. 2016 Jan;101(1):275-83. doi: 10.1210/jc.2015-3095. Epub 2015 Nov 17.

  PMID: 26574954 BACKGROUND

• Rappou E, Jukarainen S, Rinnankoski-Tuikka R, Kaye S, Heinonen S, Hakkarainen A, Lundbom J, Lundbom N, Saunavaara V, Rissanen A, Virtanen KA, Pirinen E, Pietilainen KH. Weight Loss Is Associated With Increased NAD(+)/SIRT1 Expression But Reduced PARP Activity in White Adipose Tissue. J Clin Endocrinol Metab. 2016 Mar;101(3):1263-73. doi: 10.1210/jc.2015-3054. Epub 2016 Jan 13.

  PMID: 26760174 BACKGROUND

• Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47. doi: 10.1016/j.cmet.2012.04.022.

  PMID: 22682224 BACKGROUND

• Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016 May 27;6:26933. doi: 10.1038/srep26933.

  PMID: 27230286 BACKGROUND

• Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. eCollection 2017.

  PMID: 29211728 BACKGROUND

MeSH Terms

Conditions

Obesity; Metabolic Syndrome; Mitochondrial Diseases

Interventions

nicotinamide-beta-riboside

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases

Study Officials

• Kirsi H Pietiläinen, MD PhD

  University of Helsinki

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in Clinical Metabolism

Model Details: Study with two interventions in healthy monozygotic twin pairs. In the first intervention, both members of BMI-discordant monozygotic twins are treated with Nicotinamide Riboside (NR). With this unique model, the investigators obtain the information on how beneficial NR is in two different BMI classes (obese and leaner) with an identical genomic background. In the second intervention, monozygotic twins concordant for body weight are selected and randomized to treatment. One member of the twin pair is treated with NR while the other co-twin gets placebo. With the twin set-up, the investigators can detect a significant treatment effect, and the heritability of NR treatment can be estimated as well.

Study Record Dates

• First Submitted: January 10, 2019
• First Posted: May 15, 2019
• Study Start: May 25, 2016
• Primary Completion: May 31, 2019
• Study Completion: May 31, 2019
• Last Updated: December 24, 2019

Record last verified: 2019-12