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Effects of Niacin on Intramyocellular Fatty Acid Trafficking in Upper Body Obesity and Type 2 Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT03867500
Recruitment Status : Recruiting
First Posted : March 8, 2019
Last Update Posted : March 8, 2019
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Michael D. Jensen, Mayo Clinic

Brief Summary:

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for the abnormal response to insulin. Likewise, the investigators do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. The investigators will measure muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates under both saline control (high overnight FFA) and after an overnight infusion of intravenous niacin (lower/normal FFA) to provide the first integrated examination of the interaction between FFA and muscle insulin action from the whole body to the cellular/molecular level. By identifying which steps in the insulin signaling pathway are most affected, the investigators will determine the site-specific effect of ceramides and/or DG on different degrees of insulin resistance.

Hypothesis 1: Greater trafficking of plasma FFA into intramyocellular DG will impair proximal insulin signaling and reduce muscle glucose uptake.

Hypothesis 2: Lowering FFA in UBO and T2DM by using an intravenous infusion of niacin will alter trafficking of plasma FFA into intramyocellular ceramides in a way that will improve insulin signaling and increase muscle glucose uptake.

Hypothesis 3: Lowering FFA in UBO and T2DM by using an intravenous infusion of niacin will alter trafficking of plasma FFA into intramyocellular DG in a way that will improve insulin signaling and increase muscle glucose uptake.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Obesity Drug: Niacin Other: Saline Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

This study is a randomized, saline control trial of the effects of niacin on intracellular fatty acid trafficking in insulin resistant states. Subjects will be screened at outpatient clinic visit appointments and interested qualified subjects will be consented and offered participation in this trial. Once consent has been obtained baseline values will be established and subjects will begin treatment and follow-up for up to the next 8 weeks.

A final evaluation and collection of lab samples will be conducted at the end of the study.

Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Effects of Niacin on Intramyocellular Fatty Acid Trafficking in Upper Body Obesity and Type 2 Diabetes Mellitus
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Niacin
Intravenous niacin infusion
Drug: Niacin
All participants will receive intravenous Niacin and each participant will serve as their own saline control on the second study

Placebo Comparator: Saline
Intravenous saline infusion
Other: Saline
All participants will serve as their own controls with a saline infusion study day.




Primary Outcome Measures :
  1. Difference in insulin-stimulated glucose disposal between overnight saline control study and overnight/insulin clamp niacin infusion study. [ Time Frame: 18 hours ]
    Glucose disposal rates will be measured in upper body obese and type 2 diabetic volunteers using hyperinsulinemic, euglycemic clamp under saline control conditions and during an intravenous infusion of niacin. Blood, muscle and fat samples will be collected on both study days, the first after an intravenous infusion of C13-labelled palmitate to measure enrichment in plasma palmitate and intramyocellular ceramides, diacylglycerols, long-chain acylcarnitines, and triglycerides under fasting conditions. The second biopsies will be at the end of the insulin clamp during which the volunteers will receive an intravenous infusion of D-9 palmitate to all enrichment measures during the insulin clamp. Measures of the insulin signaling (and other) pathway(s) will be made on both muscle and adipose biopsy samples collected on both study days. Adipose samples will be processed to measure morphology and function of adipocytes.

  2. Difference in insulin-stimulated phosphorylation of insulin-responsive signaling molecules between overnight saline control study and overnight/insulin clamp niacin infusion study. [ Time Frame: 18 hours ]
    Glucose disposal rates will be measured in upper body obese and type 2 diabetic volunteers using hyperinsulinemic, euglycemic clamp under saline control conditions and during an intravenous infusion of niacin. Blood, muscle and fat samples will be collected on both study days, the first after an intravenous infusion of C13-labelled palmitate to measure enrichment in plasma palmitate and intramyocellular ceramides, diacylglycerols, long-chain acylcarnitines, and triglycerides under fasting conditions. The second biopsies will be at the end of the insulin clamp during which the volunteers will receive an intravenous infusion of D-9 palmitate to all enrichment measures during the insulin clamp. Measures of the insulin signaling (and other) pathway(s) will be made on both muscle and adipose biopsy samples collected on both study days. Adipose samples will be processed to measure morphology and function of adipocytes.

  3. Difference in incorporation of 13-palmitate and D9-palmitate into intramyocellular lipid intermediates between overnight saline control study and overnight/insulin clamp niacin infusion study. [ Time Frame: 18 hours ]
    Glucose disposal rates will be measured in upper body obese and type 2 diabetic volunteers using hyperinsulinemic, euglycemic clamp under saline control conditions and during an intravenous infusion of niacin. Blood, muscle and fat samples will be collected on both study days, the first after an intravenous infusion of C13-labelled palmitate to measure enrichment in plasma palmitate and intramyocellular ceramides, diacylglycerols, long-chain acylcarnitines, and triglycerides under fasting conditions. The second biopsies will be at the end of the insulin clamp during which the volunteers will receive an intravenous infusion of D-9 palmitate to all enrichment measures during the insulin clamp. Measures of the insulin signaling (and other) pathway(s) will be made on both muscle and adipose biopsy samples collected on both study days. Adipose samples will be processed to measure morphology and function of adipocytes.


Secondary Outcome Measures :
  1. Effects of niacin on adipocyte lipolysis proteins [ Time Frame: 18 hours ]
    Glucose disposal rates will be measured in upper body obese and type 2 diabetic volunteers using hyperinsulinemic, euglycemic clamp under saline control conditions and during an intravenous infusion of niacin. Blood and fat samples will be collected on both study days, the first after an intravenous infusion of C13-labelled palmitate and the second at the end of the insulin clamp during which the volunteers will receive an intravenous infusion of D-9 palmitate during the insulin clamp. Measures of the insulin signaling (and other) pathway(s) will be made on both adipose biopsy samples collected on both study days. Adipose samples will be processed to measure morphology and function of adipocytes. We will measure the phosphorylation of insulin-regulated and niacin-regulated lipolysis proteins on both study days and on both adipose biopsies.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

  • Women and Men (Women premenopausal)
  • BMI 29-37
  • Weight stable
  • Not pregnant/nursing

Exclusion criteria:

  • Ischemic heart disease
  • Atherosclerotic valvular disease
  • Smokers (>20 cigarettes per week)
  • Bilateral oophorectomy
  • Concomitant use of medications that can alter serum lipid profile:

    • High dose fish oil (>3g per day),
    • STATINS (if yes hold for 6 weeks and receive PCP's approval),
    • Niacin
    • Fibrates
    • thiazolidinediones
    • Beta-blockers
    • Atypical antipsychotics
  • Lidocaine or Niacin/Niaspan allergy
  • Subjects with 1.5 times upper limit of normal of serum creatinine, Alkaline phosphatase, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) unless participant has fatty liver disease, Total bilirubin (unless the patient has documented Gilbert's syndrome)

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): NCT03867500


Contacts
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Contact: Sarah C Wolhart, BSN 507-255-6940 wolhart.sarah@mayo.edu

Locations
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United States, Minnesota
Mayo Clinic in Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Pamela A Reich, SC    507-255-6062    reich.pamela@mayo.edu   
Principal Investigator: Michael D jensen, MD         
Sponsors and Collaborators
Mayo Clinic
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Michael D Jensen Mayo Clinic

Additional Information:
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Responsible Party: Michael D. Jensen, Principle Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT03867500     History of Changes
Other Study ID Numbers: 17-009977
5R01DK045343-27 ( U.S. NIH Grant/Contract )
First Posted: March 8, 2019    Key Record Dates
Last Update Posted: March 8, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Obesity
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Niacin
Niacinamide
Nicotinic Acids
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Vasodilator Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs