Dietary Lipid Induced Insulin Resistance

Mechanisms of Dietary Lipid Induced Insulin Resistance

The overall goal of the proposal is to use a saturated fatty acid (SFA)- enriched, high fat diet to rapidly induce insulin resistance (IR) to provide insight into underlying proximal mechanisms of reduced insulin signaling. Specifically, investigators will identify the initial changes in metabolite concentrations/or pathway signaling ("pathways" will be used to broadly refer to these mechanism specific measures) and therefore the mechanisms most likely responsible for the development of IR during this high fat nutritional challenge. Investigators have assembled a multidisciplinary team that is versed with dietary studies, fatty acid metabolism, measurement of IR and potential mechanisms and mediators of IR, and has experience working with monocytes and the two tissues, muscle and adipose tissue, that are particularly relevant for understanding the effects of high fat diets on IR.

Study Overview

• Status: Unknown
• Conditions: Insulin Resistance
• Intervention / Treatment: Other: SFA diet; Other: MUFA diet; Other: CARB diet

Detailed Description

In the first aim, investigators will test whether a short-term high SFA-diet induces and increases insulin resistance in participants with normal and abnormal glucose tolerance, respectively, and determine the associated changes in muscle, adipose tissue and inflammatory cell composition, pathway activation and insulin signaling. Investigators will identify changes in specific signal pathways within these tissues and cells that are hypothesized to mediate or modulate insulin action. Primary mechanisms and pathways examined will include local tissue and systemic inflammation, formation of bioactive lipid intermediates, generation of endoplasmic reticulum (ER) stress, and mitochondrial dysfunction/reactive oxygen formation. By performing studies in participants with normal glucose tolerance and in those with abnormal glucose tolerance investigators will also determine whether the extent and mechanisms of insulin resistance vary with initial degrees of glucose intolerance.

In the second aim, to determine if the extent and mechanisms of insulin resistance vary with dietary composition, investigators will determine whether diets of similar caloric content as the SFA-diet, but enriched in monounsaturated fatty acids or carbohydrates, also induce insulin resistance and whether similar or different mechanistic pathways are responsible. Identifying similarities and differences between diets in inflammatory cell and tissue changes and comparing their relationships with peripheral and tissue insulin action will further clarify which cell and tissue events are most closely linked to development of insulin resistance.

In the final aim, to identify the temporal sequence of mechanistic pathways for insulin resistance and the role of cell and tissue cross-talk in these events, investigators will evaluate inflammatory cell, skeletal muscle and adipose tissue composition and pathway changes after acute, subacute, and more chronic dietary challenges in the same individuals. This will also permit assessment of whether repeated dietary challenges create changes in tissues that resemble those found in more chronic and advanced states of insulin resistance.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Carl T. Hayden VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body mass index (BMI) from 25-35 kg/m2
• normal glucose tolerance (NGT) diagnosis based on fasting glucose value 100mg/dl and 2 hr glucose <140 mg/dl after a standard 75 gm glucose load; impaired fasting glucose (IFG) on fasting glucose value ≥100 and <126 mg/dl and 2 hr glucose <140 mg/dl; impaired glucose tolerance (IGT) based on 2 hr glucose ≥140 and <200 mg/dl and a fasting glucose <126 mg/dl
• Fasting triglyceride levels <500 mg/dl

Exclusion Criteria:

• Type 1 or 2 diabetes mellitus or a hemoglobin A1c value ≥ 6.5 mg/dl
• Any diabetes medications in the past month, thiazolidinedione medications in the prior 3 months or prior regular use of insulin
• Use of diets, medications (e.g., steroids, weight loss medications ) or current or planned behavior changes (e.g. acute weight loss, exercise training) that will influence changes in IR
• Creatinine >2.0 mg/dl or other laboratory evidence of significant active disease, including hepatic enzyme elevation >2x normal and anemia, known "Nonalcoholic Fatty Liver Disease", bleeding risk
• Malabsorption of fat or other nutrients, severe lactose intolerance or other significant gastrointestinal or pancreatic problems, or recent history of nausea or vomiting
• Acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
• Cardiovascular event, stable or unstable angina or other major illness in the past 6 months
• Current regular use of anti-inflammatory medications (e.g. salicylates > 1 gm/ day) or antioxidants in excess of a daily multi-vitamin, including supplements (e.g. fish oils)
• Lipid lowering medications must be at a stable dose for at least 2 months prior to participation
• Ethanol consumption more than 4 oz day; more than occasional smoker
• Reproductively active women not on contraceptives
• Known allergies, prior reactions or contraindications to proposed clinical agents (e.g Octreotide)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SFA versus control diet; Participants will be randomized in a cross-over design to either a weight-maintaining, nutritionally-balanced American Heart Association based eucaloric control diet or a high calorie 24-hour saturated fatty acids enriched diet. For the control diet participants will follow a dietary plan for 72 hours prior to testing. For the SFA diet, participants will be provided with high caloric liquid shakes for breakfast, lunch, dinner and a bedtime snack. On the morning of each test day, participants will be admitted in the fasting state and will provided with a breakfast meal corresponding to the assigned diet (SFA or control). Three hours after completion of the meal, insulin sensitivity will be measured by insulin-suppression test (IST).	Other: SFA diet; SFA versus control diet
Experimental: MUFA versus control diet; Participants will be randomized in a cross-over design to either a weight-maintaining, nutritionally-balanced American Heart Association based eucaloric control diet or a high calorie 24-hour monounsaturated fatty acids (MUFA) enriched diet. For the control diet participants will follow a dietary plan for 72 hours prior to testing. For the MUFA diet, participants will be provided with high caloric liquid shakes for breakfast, lunch, dinner and a bedtime snack. On the morning of each test day, participants will be admitted in the fasting state and will provided with a breakfast meal corresponding to the assigned diet (MUFA or control). Three hours after completion of the meal, insulin sensitivity will be measured by insulin-suppression test (IST).	Other: MUFA diet; MUFA versus control diet
Experimental: CARB versus control diet; Participants will be randomized in a cross-over design to either a weight-maintaining, nutritionally-balanced American Heart Association based eucaloric control diet or a high calorie 24-hour carbohydrate (CARB) enriched diet. For the control diet participants will follow a dietary plan for 72 hours prior to testing. For the CARB diet, participants will be provided with high caloric liquid shakes for breakfast, lunch, dinner and a bedtime snack. On the morning of each test day, participants will be admitted in the fasting state and will provided with a breakfast meal corresponding to the assigned diet (CARB or control). Three hours after completion of the meal, insulin sensitivity will be measured by insulin-suppression test (IST).	Other: CARB diet; CARB versus control diet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Steady-state plasma glucose (SSPG)	Average plasma glucose concentrations during min 150-180 of the insulin suppression test (IST)	150-180 min

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acylcarnitine species	Measured by chromatography electrospray ionization mass spectrometry on plasma and skeletal muscle samples.	Overnight fast, 3-hour post breakfast
Diacylglycerol species	Measured on plasma, skeletal muscle and subcutaneous adipose tissue samples.	Overnight fast, 3-hour post breakfast
Ceramides species	Measured on plasma, skeletal muscle and subcutaneous adipose tissue samples.	Overnight fast, 3-hour post breakfast
Insulin signaling proteins	Measured on skeletal muscle and subcutaneous adipose tissue samples.	Overnight fast, 3-hour post breakfast
Inflammation markers	Cytokines and adipokines will be measured in plasma after the diet treatments by ELISA techniques. Mononuclear cells inflammatory gene expression will be measured by real time polymerase chain reaction (RT-PCR). Inflammation will be measured in muscle and adipose tissue by RT-PCR and Western blood analysis.	Overnight fast, 3-hour post breakfast

Collaborators and Investigators

• Sponsor: Phoenix VA Health Care System
• Investigators: Principal Investigator: Peter D Reaven, MD, Phoenix Veterans Affairs Health Care System

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Anticipated): July 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: April 27, 2016
• First Posted (Estimate): May 2, 2016

Study Record Updates

• Last Update Posted (Actual): August 1, 2019
• Last Update Submitted That Met QC Criteria: July 31, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: saturated fat; acute insulin resistance; insulin suppression test; dietary fatty acids
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: 029

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Subject to VA regulation.