Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes

Abstract

Aims/hypothesis Microvascular blood flow (MBF) increases in skeletal muscle postprandially to aid in glucose delivery and uptake in muscle. This vascular action is impaired in individuals who are obese or have type 2 diabetes. Whether MBF is impaired in normoglycaemic people at risk of type 2 diabetes is unknown. We aimed to determine whether apparently healthy people at risk of type 2 diabetes display impaired skeletal muscle microvascular responses to a mixed-nutrient meal. Methods In this cross-sectional study, participants with no family history of type 2 diabetes (FH−) for two generations (n = 18), participants with a positive family history of type 2 diabetes (FH+; i.e. a parent with type 2 diabetes; n = 16) and those with type 2 diabetes (n = 12) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin and indirect calorimetry) were measured before and during the MMC. Skeletal muscle large artery haemodynamics (2D and Doppler ultrasound, and Mobil-O-graph) and microvascular responses (contrast-enhanced ultrasound) were measured at baseline and 1 h post MMC. Results Despite normal blood glucose concentrations, FH+ individuals displayed impaired metabolic flexibility (reduced ability to switch from fat to carbohydrate oxidation vs FH−; p < 0.05) during the MMC. The MMC increased forearm muscle microvascular blood volume in both the FH− (1.3-fold, p < 0.01) and FH+ (1.3-fold, p < 0.05) groups but not in participants with type 2 diabetes. However, the MMC increased MBF (1.9-fold, p < 0.01), brachial artery diameter (1.1-fold, p < 0.01) and brachial artery blood flow (1.7-fold, p < 0.001) and reduced vascular resistance (0.7-fold, p < 0.001) only in FH− participants, with these changes being absent in FH+ and type 2 diabetes. Participants with type 2 diabetes displayed significantly higher vascular stiffness (p < 0.001) compared with those in the FH− and FH+ groups; however, vascular stiffness did not change during the MMC in any participant group. Conclusions/interpretation Normoglycaemic FH+ participants display impaired postprandial skeletal muscle macro-and microvascular responses, suggesting that poor vascular responses to a meal may contribute to their increased risk of type 2 diabetes. We conclude that vascular insulin resistance may be an early precursor to type 2 diabetes in humans, which can be revealed using an MMC.

Oral and intravenous glucose administration elicit opposing microvascular blood flow responses in skeletal muscle of healthy people: role of incretins

“…2016), have a parent with type 2 diabetes (Russell et al . 2022) or themselves have type 2 diabetes (Emanuel et al . 2018), positioning the skeletal muscle microvasculature as an important physiological tissue for human metabolism.…”

“…This increase in skeletal muscle MBF promotes nutrient and hormone delivery to the myocyte (reviewed in (Clark, 2008;Wagenmakers, 2016)) and contributes to 40-50% of insulin-stimulated skeletal muscle glucose disposal (Vincent et al 2003;Vincent et al 2004). This favourable vascular response is blunted in individuals that are obese (Clerk et al 2006;Keske et al 2009;Meijer et al 2015;Wang et al 2020), have metabolic syndrome (Jahn et al 2016), have a parent with type 2 diabetes (Russell et al 2022) or themselves have type 2 diabetes (Emanuel et al 2018), positioning the skeletal muscle microvasculature as an important physiological tissue for human metabolism.…”

The impact of family history of type 2 diabetes on clinical heterogeneity in idiopathic type 1 diabetes

“…Several studies have been conducted to investigate the potential mechanisms underlying the aforementioned implications of family history of T2D. Reduced metabolic rate, 50,51 increased ectopic lipid deposition after fructose overconsumption, 48 and higher weight and fat gain induced by experimental overfeeding 46 were found in healthy individuals with a family history of T2D, indicating that they are more susceptible to metabolic decompensation and insulin resistance. Genetic differences, such as lower gene expression of adiponectin receptors 52 and T2D‐associated gene variants, 53 are also the underlying causes of the insulin resistance associated with family history of T2D.…”

Insulin Resistance in the Brain: Evidence Supporting a Role for Inflammation, Reactive Microglia, and the Impact of Biological Sex

“…How much insulin is released into the bloodstream is tightly coupled to blood glucose concentrations, thus enabling exquisite control of glucose homeostasis at any given time. Obesity is the major risk factor for developing insulin resistance -a condition where the body becomes less sensitive to the actions of insulin [17][18][19][20][21][22]. From a metabolic perspective, insulin resistance leads to reduced insulin-mediated suppression of hepatic glucose output as well as reduced insulin-mediated glucose uptake by skeletal muscle and adipose tissue [18,21].…”