Microvascular Dysfunction and the Development of Whole-body Insulin Resistance (DESIRE)

July 25, 2017 updated by: Erik Serne, Amsterdam UMC, location VUmc

Is Microvascular Dysfunction an Early Phenomenon in the Development of Skeletal Muscle Insulin Resistance? A Dietary Intervention Study in Healthy Men

This study aims to elucidate the role of the microcirculation in the development of whole body insulin resistance. The investigators hypothesize that impaired insulin signaling in the vasculature is an early phenomenon in the development of whole body insulin resistance. Furthermore, the investigators aim to identify improvement of microvascular function as a potential target in diabetes prevention and treatment.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In today's society, food availability grossly exceeds our body's caloric demands. Excessive caloric intake causes weight gain and induces insulin resistance, a common characteristic of obesity and major risk factor for type 2 diabetes (T2DM) and cardiovascular disease.

The primary targets of insulin action are skeletal muscle, adipose tissue and the liver, but recent data point to the vascular endothelium as an important target. Insulin directly targets the endothelial cell where it activates phosphoinositide 3-kinase, resulting in Akt-mediated phosphorylation of endothelial nitric oxide synthase (eNOS). This leads to NO production - a potent vasodilator in the human body. Simultaneously insulin also activates the mitogen-activated protein kinase pathway in endothelial cells, which enhances the generation of the vasoconstrictor endothelin-1 via extracellular signal-regulated kinases 1/2 signaling. Via these two pathways insulin can regulate vascular tone.

In healthy individuals, insulin signaling in the endothelial cell leads to capillary recruitment in skeletal muscle tissue via vasodilatation of terminal arterioles. It has been proposed that insulin in this matter regulates the delivery of insulin and glucose to skeletal muscle by increasing endothelial surface area. In obese individuals and patients with T2DM, insulin-mediated capillary recruitment in skeletal muscle tissue is impaired and insulin-dependent glucose uptake is diminished. Whether these two processes are linked or occur in parallel remains unknown.

Interestingly, studies in rodents demonstrated that during obesity induced by high fat feeding, insulin resistance develops in the vasculature before these responses are detected in muscle, liver, or adipose tissue. Therefore, insulin signaling in endothelium might change in response to a positive energy balance to prevent nutrient overload in muscle and optimize nutrient storage in adipose tissue. Conversely, it has been hypothesized that early reversal of endothelial insulin resistance could prevent peripheral insulin resistance, assuming a cause-and-effect relationship between these processes. The most compelling evidence for this hypothesis came from studies in endothelial cell specific insulin receptor substrate-2 (IRS-2) knock-out mice. Kubota et al. demonstrated that impaired insulin signaling in endothelial cells, due to reduced IRS-2 expression and insulin-induced eNOS phosphorylation, caused attenuation of insulin-induced capillary recruitment and insulin delivery, which reduced glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells by infusion of beraprost sodium - a stable prostaglandin analogue - completely reversed the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking IRS-2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle was restored in these mice.

These data suggest that pharmacological stimulation of tissue perfusion may hold promise as a therapeutic strategy to increase whole body glucose disposal and thus prevent or reduce hyperglycaemia. In humans however, data linking improvement of capillary recruitment by pharmacological agents to restoration of whole-body glucose uptake are lacking. Low dose iloprost infusion - another stable prostaglandin analogue - has been shown to improve insulin-stimulated whole-body glucose uptake, but the mechanistic role of microvascular response was not assessed. Overall, it remains to be demonstrated whether improving capillary recruitment by endothelial insulin signaling or direct stimulation of smooth muscle tissue may serve as an attractive preventive or therapeutic approach to bypass cellular resistance to glucose disposal.

In conclusion, vascular insulin resistance leads to blunted capillary recruitment in the skeletal muscle and may lead to diminished glucose uptake due to a decreased capillary surface area for nutrient exchange. Up till now however it remains unclear if these processes are interrelated or occur in parallel. Evidence from animal studies suggest that vascular insulin resistance precedes diminished whole-body glucose uptake and myocellular impairments. This indicates a potential cause-effect relationship. In humans, however, this was never demonstrated. On the other hand, decreased capillary recruitment of skeletal muscle tissue could also protect muscle tissue from nutrient overload and shunt excess calories towards adipose tissue. Presently, it is unknown whether insulin redistributes blood flow from skeletal muscle to adipose tissue during hypercaloric conditions. Finally, it is unknown if stimulation of tissue perfusion with a pharmacological agent can restore whole-body glucose uptake is therefore an effective strategy in prevention or treatment of insulin resistance.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1081 HV
        • VU University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 30 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Caucasian
  • BMI 22-25 kg/m2
  • Normal insulin sensitivity as estimated by Homeostasis Model Assessment (HOMA-IR)
  • Normoglycemia as defined by fasting plasma glucose (FPG) <6.1 mmol/l
  • Normoglycemia as defined by 2 h glucose <7.8 mmol/l during oral glucose tolerance test (OGTT)
  • Normal diet pattern according to the Dutch guidelines for a healthy diet 2006
  • Stable body weight (<3% weight change) during 6 months before enrolment in the study

Exclusion Criteria:

  • Presence of any relevant disease
  • Use of any relevant medication
  • First-degree relative with type 2 diabetes
  • Smoking
  • Shift work
  • A history of chronic glucocorticoids (GC) use or GC use < 3 months ago
  • Excessive sport activities (more often than 3 hours per week)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Hypercaloric diet
Hypercaloric diet (1.6x REE) for 30 days
Dietary supplement: Hypercaloric diet
Hypercaloric diet consisting of 60% excess calories based on resting energy expenditure (REE). Calories will be provided in the form of snacks in between the ad libitum meals. A subsequent hypocaloric diet will consist of 1.0x resting energy expenditure.
Placebo Comparator: Normal diet
Normocaloric diet (1.0xREE)
Other: Normocaloric diet
Normocaloric diet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Microvascular Insulin Sensitivity
Time Frame: Baseline, 7-10 days after initiation of the hypercaloric diet, after the hypercaloric diet, after the subsequent hypocaloric diet
Capillary recruitment by contrast-enhanced ultrasound.
Baseline, 7-10 days after initiation of the hypercaloric diet, after the hypercaloric diet, after the subsequent hypocaloric diet

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Whole Body Insulin Sensitivity
Time Frame: Baseline, 7-10 days after initiation of the hypercaloric diet, after the hypercaloric diet,
M-value by euglycemic-hyperinsulinemic clamp
Baseline, 7-10 days after initiation of the hypercaloric diet, after the hypercaloric diet,

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Amsterdam UMC, location VUmc

Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Investigators

  • Principal Investigator: Erik Serne, MD PhD, Amsterdam UMC, location VUmc

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2015

Primary Completion (Actual)

May 30, 2017

Study Completion (Actual)

May 30, 2017

Study Registration Dates

First Submitted

March 10, 2015

First Submitted That Met QC Criteria

December 8, 2015

First Posted (Estimate)

December 11, 2015

Study Record Updates

Last Update Posted (Actual)

July 26, 2017

Last Update Submitted That Met QC Criteria

July 25, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DC2014DES001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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