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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Niacin; Drug: Saline

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Niacin then saline; All participants will receive intravenous Niacin overnight on day one and then intravenous saline overnight on the second study day	Drug: Niacin; Intravenous infusion, a titrated dose starting from 0.6 mg/min to a maximum of 2.8 mg/min (likely needed dose = 1.4 mg/min); Drug: Saline; Intravenous infusion of 0.9% Sodium chloride (NaCl)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose Infusion Rate	Glucose infusion 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. The hyperinsulinemic-euglycemic clamp is a method used to measure insulin sensitivity. Plasma insulin concentration is acutely raised and maintained at ~40-80 μU/ml (microunits per milliliter) by continuous insulin infusion. During the clamp, the plasma glucose concentration was held constant at normal blood sugar level. The glucose infusion rate over the last hour of the insulin infusion is the net effect of insulin on whole-body glucose metabolism. This rate serves as a measure of tissue insulin sensitivity. The hyperinsulinemic-euglycemic clamp assesses how sensitive your tissues are to insulin.	18 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of niacin on adipocyte lipolysis proteins	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.	18 hours

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Michael D Jensen, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Actual): December 22, 2021
• Study Completion (Actual): December 22, 2021

Study Registration Dates

• First Submitted: January 25, 2019
• First Submitted That Met QC Criteria: March 7, 2019
• First Posted (Actual): March 8, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 15, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Overweight; Obesity; Diabetes Mellitus, Type 2; Diabetes Mellitus; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Micronutrients; Vitamin B Complex; Vitamins; Vasodilator Agents; Hypolipidemic Agents; Lipid Regulating Agents; Niacin
• Other Study ID Numbers: 17-009977; 5R01DK045343 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No