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: Suspended
• Conditions: Obesity; Type 2 Diabetes Mellitus
• Intervention / Treatment: Other: Saline; Drug: Niacin

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Sarah C Wolhart, BSN; Phone Number: 507-255-6940; Email: wolhart.sarah@mayo.edu

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
• Genders Eligible for Study: All

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: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in insulin-stimulated glucose disposal between overnight saline control study and overnight/insulin clamp niacin infusion study.	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.	18 hours
Difference in insulin-stimulated phosphorylation of insulin-responsive signaling molecules between overnight saline control study and overnight/insulin clamp niacin infusion study.	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.	18 hours
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.	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.	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)

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Anticipated): July 1, 2024
• Study Completion (Anticipated): July 1, 2024

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): April 7, 2023
• Last Update Submitted That Met QC Criteria: April 5, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Obesity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Niacin
• Other Study ID Numbers: 17-009977; 5R01DK045343-27 (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