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

Overview

About this study

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, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We 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, we 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Males and females between 18 and 65 years of age.
  • Able to comprehend instructions, follow study procedures.
  • Willing to sign an informed consent form.
  • Willing to consume an isoenergetic diet eating all meals from Mayo GCRC for at least 3 days prior to study.
  • Overweight/Obese volunteers will have a BMI 29.0 – 40.0 kg/m^2:
  • Upper body/visceral obesity (UBO) in women will be those with a waist-hip ratio (WHR) > 0.85 and/or increased visceral fat by single slice CT scan and/or biochemical evidence of metabolic syndrome. 
  • Upper body obesity in men will be defined as a waist-hip ratio of > 0.95 and/or increased visceral fat by single slice CT scan and/or biochemical evidence of metabolic syndrome.
  • Volunteers with Type 2 Diabetes will have HbA1C from 6.5-11.5%.
  • Hold metformin and sulfonylurea for 1 week prior study.
  • Avoid pioglitazone due to long half life.
  • Resting vital signs are within the following range:
    • 95 mmHg < systolic blood pressure < 160 mmHg;
    • 45 mmHg < diastolic blood pressure < 100 mmHg;
    • 40 bpm < heart rate < 100 bpm;
    • Weight stable +0.3 kg for 2 months.
  • Female subjects are eligible if they meet the following criteria:
    • Are not pregnant or nursing;
    • All women of childbearing potential will have a negative serum pregnancy test at screening and a negative urine pregnancy test within 48 hours before administering study drug;
    • All women of childbearing potential will use an appropriate contraceptive method including barrier method, oral contraceptive medication, contraceptive device or abstinence while participating in the study.
  • Recent or current research participation:
    • If Yes look at consent form and f/u visits:
    • Medications that alter fat metabolism possibly given: if yes, exclude.
    • Weight possible changing in the study.
    • Amount of blood drawn during the study (if our study plus this one draw ≥ 450 ml these should be separated by 8 weeks.
    • Previous labs:
      • HbA1C < 6.5% for non-diabetic UBO;
      • Fasting glucose < 126 mg/dl for non-diabetic UBO;
      • Hb ≥ 11.0 for women and ≥ 12 for men;
      • Platelets > 100000.

Exclusion Criteria:

  • Individuals with a history of a disease process such as:
    • Ischemic heart disease;
    • Atherosclerotic valvular disease.
    • Blood pressure greater than 160/95 despite antihypertensive medication.
  • Smokers > 20 cigarettes per week.
  • Concomitant use of medications that can alter serum lipid profile:
    • High dose fish;
    • il (> 3g per day);
    • STATINS (if yes hold for 6 weeks and receive PCP’s approval);
    • Niacin;
    • Fibrates;
    • Beta-blockers;
    • Atypical antipsychotics;
    • Antidepressants that cause weight gain if newly prescribed or not weight stable for 1 year;
  • Allergy to Lidocaine, niacin and/or Niaspan;
  • Subjects with any of the following parameters greater than 1.5 times the upper limit of normal:
    • Serum creatinine;
    • Alkaline phosphatase;
    • Aspartate aminotransferase (AST) unless participant has fatty liver disease, in which case AST can be < 2 times upper limit normal;
    • Alanine aminotransferase (ALT) unless participant has fatty liver disease, in which case AST can be < 2 times upper limit normal;
    • Total bilirubin (unless the patient has documented Gilbert’s syndrome).
  • Subjects with any laboratory outside the normal range, unless determined by the investigator that the abnormality is not clinically significant for an obese or diabetic, but otherwise healthy subject.

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Michael Jensen, M.D.

Contact us for the latest status

Contact information:

Pamela Reich

(507) 255-6062

Reich.Pamela@mayo.edu

More information

Publications

Publications are currently not available
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CLS-20432035

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