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

Study Overview
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Brief Summary
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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.

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

Conditions
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Type 2 Diabetes Mellitus, Obesity

Intervention / Treatment
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* Drug: Niacin
* Other: Saline


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niacin<br>Intravenous niacin infusion | Drug: Niacin<br>* All participants will receive intravenous Niacin and each participant will serve as their own saline control on the second study<br>|
| Placebo Comparator: Saline<br>Intravenous saline infusion | Other: Saline<br>* All participants will serve as their own controls with a saline infusion study day.<br>|

What is the study measuring?
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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 |