We conclude that insulin enhances arterial endothelial function in health but not in METSYN, and this vascular insulin resistance may underlie its increased cardiovascular disease risk.

Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may themselves alter vascular function.r No prior studies have examined the effect of acute hyperglycaemia on both macro-and microvascular function while controlling plasma insulin concentrations.r Macrovascular and microvascular functional responses to euglycaemia and hyperglycaemia were compared. Octreotide was infused throughout both protocols to prevent endogenous insulin release.r Acute hyperglycaemia (induced by intravenous glucose) enhanced brachial artery flow-mediated dilatation, increased skeletal muscle microvascular blood volume and flow, and expanded cardiac muscle microvascular blood volume.r Compared to other published findings, the results suggest that vascular responses to acute hyperglycaemia differ based on the study population (i.e. normal weight vs. overweight/obese) and/or glucose delivery method (i.e. intravenous vs. oral glucose).

Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans. RESEARCH DESIGN AND METHODSFifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined. RESULTSInsulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by ∼30% and ∼40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by ∼20%. Insulin, GLP-1, and GLP-1 1 insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes. CONCLUSIONSIn obese humans with microvascular insulin resistance, GLP-1's vasodilatory actions are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.

Diabetes mellitus accelerates vascular disease through multiple biochemical pathways driven by hyperglycemia, with insulin resistance and/or hyperinsulinemia also contributing. Persons with diabetes mellitus experience premature large vessel and microvascular disease when compared to normoglycemic controls. Currently there is a paucity of clinical data identifying how acutely the vasculature responds to hyperglycemia and whether other physiologic factors (e.g., vasoactive hormones) contribute. To our knowledge, no prior studies have examined the dynamic effects of acute hyperglycemia on insulin-mediated actions on both micro- and macrovascular function in the same subjects. In this randomized crossover trial, healthy young adults underwent two infusion protocols designed to compare the effects of insulin infusion during euglycemia and hyperglycemia on micro- and macrovascular function. Both euglycemic- and hyperglycemic-hyperinsulinemia increased skeletal (but not cardiac) muscle microvascular blood volume (each p<0.02) and blood flow significantly (each p<0.04), and these increases did not differ between protocols. Hyperglycemic-hyperinsulinemia trended towards increased carotid-femoral pulse wave velocity (indicating increased aortic stiffness; p= 0.065 after Bonferroni adjustment), while euglycemic-hyperinsulinemia did not. There were no changes in post-ischemic flow velocity or brachial artery flow-mediated dilation during either protocol. Plasma endothelin-1 levels significantly decreased during both protocols (each p<0.02). In this study, acute hyperglycemia for 4 hours did not inhibit insulin's ability to increase skeletal muscle microvascular perfusion but did provoke a slight increase in aortic stiffness. Hyperglycemia also did not adversely affect myocardial microvascular perfusion or endothelial function or prevent the decline of endothelin-1 during insulin infusion.

Background: Arterial stiffness and endothelial dysfunction are both reported in children with type 1 diabetes (DM1) and may predict future cardiovascular events. In health, nitric-oxide (NO) relaxes arteries and increases microvascular perfusion. The relationships between NO-dependent macro- and microvascular functional responses and arterial stiffness have not been studied in adolescents with DM1. Here we assessed macro- and microvascular function in DM1 adolescents and aged-matched controls at baseline and during an oral glucose challenge (OGTT). Methods: DM1 adolescents (n=16) and controls (n=14) were studied before and during an OGTT. At baseline we measured: A) large artery stiffness using both aortic augmentation index (AI) and carotid-femoral pulse wave velocity (cfPWV); B) brachial flow-mediated dilation (FMD) and forearm endothelial function using post-ischemic flow velocity (PIFV); and C) forearm muscle microvascular blood volume (MBV) using contrast-enhanced ultrasound. Following OGTT, AI, cfPWV and MBV were reassessed at 60 min and MBV again at 120 min. Within individual and between-group comparisons were made by paired and unpaired t-tests or repeated measures ANOVA. Results: Baseline FMD was lower (p=0.02) in DM1. PWV at 0 and 60 min did not differ between groups. Baseline AI did not differ between groups but declined with OGTT only in controls (p=0.02) and was lower than DM1 at 60 min (p<0.03). Baseline MBV was comparable in DM1 and control groups, but declined in DM1 at 120 min (p=0.01) and was lower than the control group (p<0.03). There was an inverse correlation between plasma glucose and MBV at 120 min (r= -0.523, p<0.01). No differences were noted between groups for VO2max (ml/min/kg), body fat (%), or BMI. Conclusions: NO-dependent macro- and microvascular function, including FMD and AI, and microvascular perfusion respectively are impaired early in the course of DM1, precede increases of arterial stiffness, and may provide an early indicator of vascular risk.

Aims: Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance has not been defined. Methods: Eleven non-diabetic, metabolic syndrome subjects were studied four times (before and after 12 weeks treatment with placebo or metformin) using a crossover design, with an eight week washout interval between treatments. On each occasion, we measured three indices of large artery function (pulse wave velocity-PWV, radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flow-mediated dilation-FMD) as well as muscle microvascular perfusion (contrast-enhanced ultrasound-CEU) before and 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. RESULTS: Metformin decreased body mass index (BMI), fat weight, and % body fat (P<0.05, each), placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate, P<0.01). PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin P<0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (P<0.02 for each) but not after metformin. CONCLUSIONS: Short-term metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhaced radial pulse wave properties consistent with relaxation of smaller arterioles.

Introduction: Increasing arterial stiffness is a feature of vascular aging that is accelerated by conditions that enhance cardiovascular risk, including diabetes mellitus. Multiple studies demonstrate divergence of carotid-femoral pulse wave velocity and augmentation index in persons with diabetes mellitus, though mechanisms responsible for this are unclear. Materials and methods: We tested the effect of acutely and independently increasing plasma glucose, plasma insulin, or both on hemodynamic function and markers of arterial stiffness (including carotid-femoral pulse wave velocity, augmentation index, forward and backward wave reflection amplitude, and wave reflection magnitude) in a four-arm, randomized study of healthy young adults. Results: Carotid-femoral pulse wave velocity increased only during hyperglycemic-hyperinsulinemia (+0.36 m/s; p = 0.032), while other markers of arterial stiffness did not change (all p > 0.05). Heart rate (+3.62 bpm; p = 0.009), mean arterial pressure (+4.14 mmHg; p = 0.033), central diastolic blood pressure (+4.16 mmHg; p = 0.038), and peripheral diastolic blood pressure (+4.09 mmHg; p = 0.044) also significantly increased during hyperglycemic-hyperinsulinemia. Conclusions: Hyperglycemic-hyperinsulinemia acutely increased cfPWV, heart rate, mean arterial pressure, and diastolic blood pressure in healthy humans, perhaps reflecting enhanced sympathetic tone. Whether repeated bouts of hyperglycemia with hyperinsulinemia contribute to chronically-enhanced arterial stiffness remains unknown.

Introduction: Increasing arterial stiffness is a feature of vascular aging that is accelerated by conditions that enhance cardiovascular risk, including diabetes mellitus. Multiple studies demonstrate divergence of carotid-femoral pulse wave velocity and augmentation index in persons with diabetes mellitus, though mechanisms responsible for this are unclear.Materials and Methods: We tested the effect of acutely and independently increasing plasma glucose, plasma insulin, or both on hemodynamic function and markers of arterial stiffness (including carotid-femoral pulse wave velocity, augmentation index, forward and backward wave reflection amplitude, and wave reflection magnitude) in a four-arm, randomized study of healthy young adults.Results: Carotid-femoral pulse wave velocity increased only during hyperglycemic-hyperinsulinemia (+0.36 m/s; p=0.032), while other markers of arterial stiffness did not change (all p>0.05). Heart rate (+3.62 bpm; p=0.009), mean arterial pressure (+4.14 mmHg; p=0.033), central diastolic blood pressure (+4.16 mmHg; p=0.038), and peripheral diastolic blood pressure (+4.09 mmHg; p=0.044) also significantly increased during hyperglycemic-hyperinsulinemia.Conclusions: Hyperglycemic-hyperinsulinemia acutely increased cfPWV, heart rate, mean arterial pressure, and diastolic blood pressure in healthy humans, perhaps reflecting enhanced sympathetic tone. Whether repeated bouts of hyperglycemia with hyperinsulinemia contribute to chronically-enhanced arterial stiffness remains unknown. (ClinicalTrials.gov number NCT03520569; registered 9 May 2018).Clinical Trial Information: ClinicalTrials.gov identifier NCT03520569 (registered 9 May 2018).