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Impact of Metabolic Health on Sperm Epigenetic Marks in Humans

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03860558
Recruitment Status : Recruiting
First Posted : March 4, 2019
Last Update Posted : March 4, 2019
Sponsor:
Information provided by (Responsible Party):
Joslin Diabetes Center

Brief Summary:
This study is designed to evaluate whether epigenetic markers in overweight men with type 1 or type 2 diabetes can be improved with a 3 month lifestyle intervention program.

Condition or disease Intervention/treatment Phase
Overweight Type 2 Diabetes Mellitus Type 1 Diabetes Mellitus Other: Lifestyle Intervention Other: No Intervention Not Applicable

Detailed Description:

Parental history of type 2 diabetes (T2D) confers substantial individual risk for development of obesity and diabetes. Obesity risk can be transmitted across generations, from parents or grandparents to children. Genomic variation explains only a portion of this risk. Epigenetic modulation through DNA methylation, histone modification, or by noncoding RNAs, provide mechanisms to regulate gene activity independent of DNA sequence by determining which genes are turned on or off in response to environment or disease. Epigenetic changes can be stable over the lifespan providing a mechanism through which environmental exposures may impart long-term effects on gene expression and phenotypic outcome.

The maternal intrauterine environment is now well recognized to modify obesity and T2D disease risk of offspring. Fetuses carried by women who are obese, diabetic or suffer from suboptimal nutrition are at increased risk of insulin resistance, obesity, T2D, and cardiovascular disease risk as adults. Studies in rodents also show that the health, metabolism, and prior environmental exposures of the male can also influence health of his offspring. Existing data provide powerful support for the hypothesis that current metabolic health of males can alter epigenetic marks in sperm and suggest a novel modifiable mechanism of transmission. However, much less is known about how human sperm epigenetic patterns change with nutritional and metabolic health, and whether these may ultimately impart differences in health of future generations.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Impact of Metabolic Health on Sperm Epigenetic Marks in Humans
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lifestyle Intervention
20 overweight men with T1D or T2D will undergo an intensive 3 month lifestyle intervention program aimed at improving metabolic health, glycemic control, and body weight.
Other: Lifestyle Intervention
Participants will undergo a 12-week multidisciplinary program for weight control and intensive diabetes management. The program includes adjustments to diabetes medications to enhance weight reduction and improve glycemia, dietary modification, and activity instructions.

Active Comparator: No-Intervention Controls
10 overweight men with T1D or T2D will be assessed at baseline and at 3 months. They will not participate in a lifestyle intervention.
Other: No Intervention
Participants will not undergo an intervention.

Active Comparator: Healthy Controls
10 healthy men will be assessed at baseline and at 3 months. They will not participate in a lifestyle intervention.
Other: No Intervention
Participants will not undergo an intervention.




Primary Outcome Measures :
  1. Spermatozoa concentration [ Time Frame: 1 year ]
    Sperm will be assessed for concentration, reported as total yield (millions per ml)


Secondary Outcome Measures :
  1. Sperm DNA methylation, reported as genomic location of regions with methylation altered in response to intervention [ Time Frame: 1 year ]
    We will utilize purified DNA (1.5 μg), sheared by sonication to obtain 200-700 bp fragments for subsequent library preparation for methylation-dependent immunoprecipitation and sequencing. Differentially methylated regions (DMR) are identified using MEDIPS. DNA methylation is assessed using sliding windows (500 bp size, 200 bp shift). Regions with read ratios >1.5 or <0.67 and binomial p<0.0001 in independent biologically replicated comparisons are designated as DMR.

  2. RNA Sequencing [ Time Frame: 1 year ]
    RNA will be isolated from sperm samples and subjected to RNA sequencing to analyze the content of both of large mRNA/noncoding RNA and small RNAs. Data will be analyzed to identify those species altered in response to intervention.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male, age 18-65 years
  • Willing and able to provide informed consent and follow all study procedures, including providing sperm specimens 3 months apart.
  • Type 1 or type 2 diabetes diagnosis confirmed by an endocrinologist (for participants in the diabetes groups)
  • HbA1c > 7% (for participants in the diabetes groups)
  • Overweight (BMI > 25 kg/m2) (for all groups, to ensure groups are similar)

Exclusion Criteria:

  • Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
  • Hepatic disease, including serum ALT or AST greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin < 3.0 g/dL; or serum bilirubin > 2.0;
  • Severe diabetic retinopathy;
  • Congestive heart failure, NYHA class II, III or IV;
  • History of myocardial infarction, unstable angina or revascularization within the past 6 months;
  • Active genitourinary infection;
  • Testicular volume <12 mL (assessed using Prader orchidometer);
  • Hypogonadism, defined as total testosterone <250 ng/dl;
  • Hyperprolactinemia, defined as prolactin >18 ng/ml;
  • Hyperestrogenism, defined as estradiol >42 pg/ml;
  • Cryptorchidism;
  • Cigarette smoking;
  • Active alcohol abuse or substance abuse;
  • Cancer (except localized non-melanoma skin cancers) or use of chemotherapy agents within 5 years;
  • Use of nitrates or guanylate cyclase stimulators;
  • Use of steroid hormones (including testosterone), other than inhalers for reactive airway disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03860558


Contacts
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Contact: Mary E Patti, MD 6173092635 mary.elizabeth.patti@joslin.harvard.edu
Contact: Elvira Isganaitis, MD elvira.isganaitis@joslin.harvard.edu

Locations
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United States, Massachusetts
Joslin Diabetes Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Mary E Patti, MD    617-309-2635    mary.elizabeth.patti@joslin.harvard.edu   
Contact: Elvira Isganaitis, MD       elvira.isganaitis@joslin.harvard.edu   
Principal Investigator: Mary E. Patti, MD         
Sub-Investigator: Elvira Isganaitis, MD         
Sponsors and Collaborators
Joslin Diabetes Center
Publications:
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Responsible Party: Joslin Diabetes Center
ClinicalTrials.gov Identifier: NCT03860558    
Other Study ID Numbers: 2015-40
First Posted: March 4, 2019    Key Record Dates
Last Update Posted: March 4, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Overweight
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Body Weight