Microvascular Blood Flow and Metabolic Flexibility in Hispanics

Cardiometabolic Health in Adult Latinos in the Rio Grande Valley With and Without Specific Gene Mutations

Sponsors

Lead Sponsor: University of Texas Rio Grande Valley

Source University of Texas Rio Grande Valley
Brief Summary

Microvascular insulin resistance has been shown to precede myocyte insulin resistance and impairments in metabolic function. However, there is no convincing data showing the relationship between impaired microvascular flow and impaired metabolic flexibility. Recent evidence exists that impaired microvascular blood flow in Caucasians directly contributes to impaired metabolic flexibility in Caucasians (under review), however there is no such evidence in Hispanics. Since there is a large disparity in cardiometabolic disease in Hispanics, this study aims to determine the role of impaired microvascular blood flow on impaired substrate oxidation switching (metabolic flexibility) in healthy people at risk for developing type 2 diabetes.

Detailed Description

Metabolic disease, including type 2 diabetes (T2D) and pre-diabetes is a significant health issue globally, particularly in the Hispanic population. The impact of this disease on morbidity and mortality is unquestionable, as it is associated with various aspects of neural and cardiovascular disease. The incidence of T2D is continually increasing, which threatens the health of future generations and poses a significant financial burden to the health care system. Early detection of "at-risk" patients could lead to more targeted treatments and improved outcomes.

The oral glucose tolerance test (GTT) is the gold standard for assessing pre-diabetes, and is used world-wide. Recent work has uncovered an important finding demonstrating that hyperglycemia from the GTT causes acute microvascular insulin resistance of skeletal muscle in healthy Caucasians, even with normal insulin response and blood glucose. It is likely that the GTT causes acute glucotoxicity which impairs normal vascular function. These findings have a significant clinical impact as they imply that the GTT does not have the sensitivity to identify people with vascular-derived insulin resistance, one of the earliest events in the development of T2D. Therefore, people with vascular-derived insulin resistance cannot be identified or diagnosed with the GTT.

An alternative test exists that has greater sensitivity to identify vascular-derived pre-diabetes than the GTT or by measuring HbA1c levels in otherwise healthy Caucasians. Using a mixed meal challenge (MMC - liquid drink comprising carbohydrate, protein and lipid) in combination with specific microvascular blood flow (MBF) and metabolic tests, MBF and metabolic abnormalities can be detected with greater sensitivity than traditional testing. However, no work in this area has been conducted in the Hispanic population. Therefore, it is important to determine if, like Caucasians, Hispanics display microvascular insulin resistance as the first step towards developing pre-diabetes.

Respiratory exchange ratio (RER) is a non-invasive test for measuring whole body fuel (carbohydrate or fat) utilization by measuring the amount of CO2 expired and the amount of O2 consumed. The ratio of these gases (or RER) gives an indication of whether a person is burning predominately fat (RER = 0.7) or carbohydrate (RER = 1.0). RER in healthy people under fasting conditions is typically ~0.75. Metabolic flexibility is the ability to switch from fat oxidation during fasting conditions to carbohydrate oxidation.

There are preliminary data showing that healthy people, who have normal glucose responses to an GTT and normal HbA1c levels , but are metabolically inflexible (MI) have a higher blood glucose excursion post-MMC when compared those who are metabolically flexible (MF) despite a similar plasma insulin excursion. Importantly, healthy MI have lower muscle microvascular perfusion post-MMC when compared to MF.

Also, the MMC distinguishes differences in carbohydrate use between these groups. The healthy MI population had a delayed switch from utilising fat to carbohydrate despite having a similar fasting respiratory exchange ratio (RER, ~0.77). This inability to switch to carbohydrate oxidation is more pronounced when expressed as the change in the RER area under the curve (AUC).

Thus, the lack of microvascular blood flow in skeletal muscle in the MI in response to the MMC is linked to the delayed ability to metabolize glucose (or carbohydrate), but not with changes in blood glucose levels. Therefore, the MMC is an alternative and more sensitive test for detecting early stages of microvascular insulin resistance that would otherwise go undetected with the GTT. However, the lack of correlation between impaired MBF in skeletal muscle during the GTT and blood glucose in some people suggest an alternate destination for glucose delivery, such as liver.

In addition, there are several genes that are associated with metabolic disease in adults and children. Lipid infusion is known to acutely impair MBF. As such, SNPs regulating lipid transport and storage are also likely to impact local MBF, though thus far remain untested. Therefore, in addition to the gold-standard MBF and metabolic assessments, genetic analysis of targeted SNPs known to affect lipid transport and storage. Cardiometabolic and genetic data will be correlated with additional lifestyle and physiological factors using non-invasive techniques to assess: a) habitual physical activity levels, b) central blood pressure and arterial stiffness, and c) skeletal muscle fiber type. These data will help explain mechanisms whereby specific genes and lifestyle combine to affect early pathophysiology of vascular-derived insulin resistance and metabolic syndrome.

Overall Status Recruiting
Start Date June 1, 2018
Completion Date December 30, 2020
Primary Completion Date December 30, 2020
Study Type Observational
Primary Outcome
Measure Time Frame
Microvascular responses in skeletal muscle 2 years
Enrollment 160
Condition
Intervention

Intervention Type: Diagnostic Test

Intervention Name: Mixed meal challenge

Description: We will conduct a traditional oral glucose tolerance test (OGTT), and compare microvascular and metabolic responses with mixed meal challenge (MMC). The procedures between the two are identical except for what is being consumed. In brief, the OGTT will be 75 g of glucose, and the MMC will be a protein shake consisting of 30g of protein, 5 g of fat, and 35g of carbohydrate. A fasting sample of blood will be collected, and the test drink (either OGTT or MMC) will be given. We will collect blood to measure glucose at: 15, 30, 60, 90, and 120 min post-drink consumption. We hypothesize that, like in Caucasians (under review), healthy Hispanics will have greater microvascular blood flow in skeletal muscle with the MMC than with OGTT, and this increased blood flow will result in greater substrate oxidation switching (metabolic flexibility).

Eligibility

Sampling Method: Non-Probability Sample

Criteria:

Inclusion Criteria:

- 18-65 years

- having either a parent with type 2 diabetes, or no history for 2 generations

- non-smoking, weight-stable

Exclusion Criteria:

- presence of microvascular disease

- smoking

- having gained or lost more than 5lbs in the last 3 months

- pregnancy

- having cancer, liver, or kidney disease within 5 years

Gender: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Contact

Last Name: Ryan D Russell, PhD

Phone: 9568826509

Email: [email protected]

Location
Facility: Status: Contact: University of Texas Rio Grande Valley - Cardiometabolic Exercise Lab Ryan D Russell, PhD 956-882-6509 [email protected]
Location Countries

United States

Verification Date

April 2018

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University of Texas Rio Grande Valley

Investigator Full Name: Ryan Russell

Investigator Title: Assistant Professor

Has Expanded Access No
Condition Browse
Arm Group

Label: FH+

Description: FH+ = having at least 1 parent with type 2 diabetes

Label: FH-

Description: FH- = having no history of type 2 diabetes for two generations (parents and grandparents)

Patient Data No
Study Design Info

Observational Model: Cohort

Time Perspective: Prospective

Source: ClinicalTrials.gov