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

NCT03867500 | Completed Early Phase 1 Results FDA Drug

• 2 other identifiers: 17-0099775R01DK045343
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus; Obesity

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (1)

Niacin then saline

EXPERIMENTAL

All participants will receive intravenous Niacin overnight on day one and then intravenous saline overnight on the second study day

Drug: Niacin; Drug: Saline

Interventions

Niacin DRUG

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)

Niacin then saline

Saline DRUG

Intravenous infusion of 0.9% Sodium chloride (NaCl)

Niacin then saline

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Mayo Clinic: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity

Interventions

Niacin; Sodium Chloride

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Michael D. Jensen, M.D.
• Organization: Mayo Clinic

jensen@mayo.edu

507-255-6515

Study Officials

• Michael D Jensen

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: January 25, 2019
• First Posted: March 8, 2019
• Study Start: November 1, 2018
• Primary Completion: December 22, 2021
• Study Completion: December 22, 2021
• Last Updated: January 17, 2025
• Results First Posted: August 6, 2024

Record last verified: 2025-01

Locations

US (1)