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

Metabolic flexibility is the ability to adjust fuel oxidation to fuel availability. The term is classically defined as the ability to switch from fat oxidation during fasting conditions to glucose oxidation during insulin stimulation (e.g. a meal, OGTT, or hyperinsulinaemic euglycaemic clamp). It is well established that people with insulin resistance and T2D are not metabolically flexible, thus do not switch oxidized fuels as efficiently as insulin sensitive individuals. However, simply looking at fasting respiratory exchange ratio (RER) is not adequate, as fasting fat oxidation can sometimes increase with the progression of T2D , lowering RER. Furthermore, people with the same fasting RER can have different degrees of metabolic flexibility, as we previously shown (Figure 5). Factors thought to mediate MF have been eloquently outlined in a perspective piece. In general, impaired MF is proposed to be caused by over-nutrition, leading to over-supply of main substrates (glucose, lipid, and amino acids) to the mitochondria, leading to disruption of signaling events mediating glucose/fatty acid oxidation switching originally proposed by Randle and colleagues. Of particular interest to this perspective of impaired MF is the requirement of either insulin resistance, or the necessity of being in a state of positive energy balance. As Dr. Russell has previously shown (Figure 5), FH+ people display similar fasting RER/RQ, but impaired MF similar to those with T2D, but with no signs of insulin resistance nor over-nutrition (as these participants were healthy, lean collegiate athletes and their collegiate athletic trainers). These data suggest that healthy FH+ develop/display impaired MF though completely different means than the current body of literature can explain. In addition, as noted in Figure 4, re-testing a similar cohort (healthy FH+/-) to compare OGTT vs MMC indicates that glucose excursions present in FH+ during the MMC are masked during an OGTT, suggesting that the MMC is more sensitive than an OGTT at detecting variations in glycemic and MBF regulation.

Skeletal Muscle Microvascular Blood Flow helps to regulate glucose disposal by increasing delivery of glucose and insulin to the myocytes. Loss of normal microvascular function is an early driver in the development of muscle insulin resistance, indicating an early therapeutic target for prevention of insulin resistance within muscle. Blocking this microvascular action of insulin (e.g. with vasoconstrictors, inflammatory cytokines, or elevated FFAs) directly cause muscle and whole body insulin resistance [8]. This microvascular action of insulin is lost during pre-diabetes and T2D in humans, though can be improved with resistance training. As there is a strong connection between skeletal muscle microvascular responses, and metabolic function (glycemic regulation and metabolic flexibility - Figure 1), we anticipate that healthy FH+ will also display impaired MBF in response to a MMC, partially explaining their metabolic dysfunction. The importance of using contrast-enhanced ultrasonography (CEU) to detect changes in MBF in real time is extremely valuable, and is discussed in the recent editorial by Dr. Linder about our April 2018 CEU paper MBF changes in adipose tissue.

Macrovascular Responses. Large blood vessel function is correlative to risk of developing hypertension and cardiovascular disease. Large blood vessel function can be measured in a number of ways including insulin-mediated dilation (degree of brachial artery dilation following an OGTT) using 2D and Doppler ultrasound. Dr. Russell has expertise in this technique in healthy, obese, and T2D populations and found that responses are improved with RT.

Recent studies from the Framingham Heart Study have indicated that large artery (aortic) stiffness precedes hypertension. Measurement of carotid-to-femoral pulse wave velocity (by applanation tonometry) is the gold standard technique to assess central artery stiffness. Drs. Russell and Karabulut have expertise in these techniques demonstrating pathologies associated with arterial stiffness.

Oral Glucose Tolerance Test (OGTT). Overnight fasted participants will undergo an OGTT in order to determine glucose tolerance intolerance. A catheter will be placed into a median deep antecubital vein for blood sampling. Each participant will consume 75g of glucose. Plasma glucose will be measured while fasting, and at 15, 30, 60, 90, and 120 min following the glucose load to measure the time course for glucose appearance/disappearance. Plasma proinsulin, insulin, C-peptide and glucagon will be measured at these times to assess pancreatic function. We will also measure glucagon-like peptide-1 (GLP-1).