Sodium glucose cotransporter 2 inhibitors (SGLT2is) improved major adverse cardiovascular events (MACE), heart failure, and renal outcomes in large trials; however, a thorough understanding of the ...vascular physiological changes contributing to these responses is lacking. We hypothesized that SGLT2i therapy would diminish vascular insulin resistance and improve hemodynamic function, which could improve clinical outcomes. To test this, we treated 11 persons with type 2 diabetes for 12 wk with 10 mg/day empagliflozin and measured vascular stiffness, endothelial function, peripheral and central arterial pressures, skeletal and cardiac muscle perfusion, and vascular biomarkers before and at 120 min of a euglycemic hyperinsulinemic clamp at
and
. We found that before empagliflozin treatment, insulin infusion lowered peripheral and central aortic systolic pressure (
< 0.05) and muscle microvascular blood flow (
< 0.01), but showed no effect on other vascular measures. Following empagliflozin, insulin infusion improved endothelial function (
= 0.02), lowered peripheral and aortic systolic (each
< 0.01), diastolic (each
< 0.05), mean arterial (each
< 0.01), and pulse pressures (each
< 0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each
= 0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each
< 0.05). We conclude that empagliflozin enhances insulin's vascular actions, which could contribute to the improved cardiorenal outcomes seen with SGLT2i therapy.
The physiological underpinnings of the cardiovascular benefits of SGLT2 inhibitors remain uncertain. We tested whether empagliflozin mitigates vascular insulin resistance in patients with type 2 diabetes. Aortic and peripheral systolic, diastolic, mean and pulse pressures, endothelial function, vascular stiffness, and heart and muscle microvascular perfusion were measured before and during an insulin infusion at baseline and after 12 wk of empagliflozin. After empagliflozin, vascular responses to insulin improved dramatically.
Key points
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.
No prior studies have examined the effect of acute hyperglycaemia on both macro‐ and microvascular function while controlling plasma insulin concentrations.
Macrovascular and microvascular functional responses to euglycaemia and hyperglycaemia were compared. Octreotide was infused throughout both protocols to prevent endogenous insulin release.
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.
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).
High glucose concentrations acutely provoke endothelial cell oxidative stress and are suggested to trigger diabetes‐related macro‐ and microvascular injury in humans. 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 each independently alter vascular function and obscure the effect of acute hyperglycaemia per se. Surprisingly, no studies have examined the acute effects of intravenous glucose‐induced hyperglycaemia on both macro‐ and microvascular function while controlling plasma insulin concentrations. In this randomized study of healthy young adults, we compared macrovascular (i.e. brachial artery flow‐mediated dilatation, carotid‐femoral pulse wave velocity and post‐ischaemic brachial artery flow velocity) and microvascular (heart and skeletal muscle perfusion by contrast‐enhanced ultrasound) functional responses to euglycaemia and hyperglycaemia. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute intravenous glucose‐induced hyperglycaemia enhanced brachial artery flow‐mediated dilatation (P = 0.004), increased skeletal muscle microvascular blood volume and flow (P = 0.001), and expanded cardiac muscle microvascular blood volume (P = 0.014). No measure of vascular function changed during octreotide‐maintained euglycaemia. Our findings suggest that unlike meal‐provoked acute hyperglycaemia, 4 h of intravenous glucose‐induced hyperglycaemia enhances brachial artery flow‐mediated dilatation, provokes cardiac and skeletal muscle microvascular function, and does not impair aortic stiffness. Previous findings of acute large artery vascular dysfunction during oral glucose or mixed meal ingestion may be due to differences in study populations and meal‐induced humoral or neural factors beyond hyperglycaemia per se. (ClinicalTrials.gov number NCT03520569.)
Introduction: Insulin exerts several opposing hemodynamic vascular actions, including stimulation of both nitric oxide-mediated vasodilation and endothelin-1-mediated vasoconstriction. Notably, ...hyperglycemia switches the vascular response to insulin from dilation to constriction in pre-clinical studies. To our knowledge, hyperglycemia’s effect on insulin’s action on vascular stiffness in humans is unknown. The American Heart Association recently recommended that vascular stiffness be determined noninvasively by carotid-femoral pulse wave velocity (cfPWV) and/or using wave separation analyses (WSA) instead of aortic augmentation index (AIx).
Methods: Thirteen lean, healthy subjects twice received a 1 mU/kg/min 2-hour insulin clamp. In one study, subjects were euglycemic and in the second, hyperglycemic (∼200 mg/dL) for 2 hours before and throughout the clamp. In each study, octreotide was infused to block endogenous insulin secretion. We assessed vascular stiffness with cfPWV, AIx, and WSA at baseline and after the 2-hour insulin clamp. Linear mixed model was used for statistical analysis, with Bonferroni correction for between-study comparisons. Spearman correlation was used to evaluate the relationship between PWV and WSA components.
Results: Compared to baseline, insulin increased cfPWV (p=0.03) during hyperglycemia without affecting AIx or components of WSA. No changes were observed during euglycemia, and insulin levels did not differ between groups. Neither AIx nor WSA components (i.e., backward and forward wave amplitude and reflection magnitude) correlated with cfPWV.
Discussion: We provide the first evidence that 4 hours of moderate hyperglycemia unmasks an action of physiologic hyperinsulinemia to increase central aortic stiffness (as measured by cfPWV) in healthy humans. Second, our results suggest that neither AIx nor WSA components correlate with cfPWV as measures of vascular stiffness.
Disclosure
W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: None.
Hypoadiponectinemia is speculated to play a key role in the relationship between obesity and COVID‐19 respiratory failure. However, only one study has examined adiponectin levels in COVID‐19 ...patients, and none have investigated adiponectin levels strictly in patients with acute respiratory failure. In this study, we performed a retrospective case‐control study of adipokine levels in patients with acute respiratory failure caused by either COVID‐19 or other viral/bacterial source. All patients with COVID‐19 respiratory failure in the University of Virginia Biorepository and Tissue Research database were included. We also selected patients with non‐COVID‐19 infectious respiratory failure from the same biorepository to serve as a comparison cohort. Plasma adipokine levels were measured on three occasions during the first 72 hours of hospitalization. Twelve patients with COVID‐19 respiratory failure and 17 patients with other infectious respiratory failure were studied. Adiponectin levels were significantly lower in patients with COVID‐19 respiratory failure, even after adjustment for age, sex, BMI, and other covariates. In conclusion, adiponectin levels appear to be reduced in COVID‐19 respiratory failure. Larger studies are needed to confirm this report.
Abstract Uncontrolled hyperglycemia in hospitalized patients with or without a previous diagnosis of diabetes is associated with adverse outcomes and longer lengths of hospital stay. It is estimated ...that one-third of hospitalized patients will experience significant hyperglycemia, and the cost associated with hospitalization for patients with diabetes accounts for half of all health care expenditures for this disease. Optimizing glycemic control should be a priority for all health care providers in the inpatient setting. Appropriate management strategies should include identification of appropriate glycemic targets, prevention of hypoglycemia, initiation of appropriate basal-plus-bolus insulin regimens, and planning for the transition from inpatient to outpatient therapy before hospital discharge.
Introduction: Chronic hyperglycemia injures both micro-and microvasculature. Conversely, insulin stimulates vascular nitric oxide production and acts as a vasodilator. Whether acute hyperglycemia ...(AH) inhibits insulin’s vasodilator action in healthy vasculature is unknown. Here we tested whether AH interfered with insulin’s action to recruit microvasculature, enhance endothelial function, or diminish vascular stiffness.
Methods: Nine healthy, fasting subjects (ages 18-35 years; BMI 18-25 kg/m2) twice received a 1 mU/kg/minute 2-hour insulin clamp. On one occasion, subjects were euglycemic (EH); and on the second, were hyperglycemic (∼200 mg/dL) (HH) for 2 hours before and throughout the clamp. Octreotide infusion blocked endogenous insulin in both studies. We assessed endothelial function by flow-mediated dilation (FMD) and arterial stiffness with pulse wave velocity (PWV) and augmentation index (AI). We used contrast-enhanced ultrasound to measure insulin-mediated capillary recruitment in skeletal and cardiac muscle. Linear mixed model was used for statistical analysis, with Bonferroni correction for comparison between studies.
Results: Insulin increased carotid-femoral PWV (p=0.02 for Δ PWV) but decreased AI (p= 0.02) during HH, with AI significantly reduced in HH compared to EH (p=0.04). Insulin recruited microvasculature (p<0.05) with either EH or HH, and microvascular blood volume (p=0.03) and blood flow (p=0.04) significantly increased in skeletal muscle after HH. No changes were observed in FMD or cardiac microvascular perfusion with either condition.
Discussion: This study provides evidence that 4 hours of AH evokes insulin-induced increases of carotid-femoral arterial stiffness in healthy subjects. Insulin’s ability to recruit microvasculature is preserved during AH.
Disclosure
W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: Research Support; Self; AstraZeneca.
Funding
National Institutes of Health (F32HL142304-01)
Insulin's microvascular actions and their relationship to insulin's metabolic actions have not been well studied in adults with type 1 diabetes mellitus (T1DM). We compared the metabolic and selected ...micro- and macrovascular responses to insulin by healthy adult control (
= 16) and subjects with T1DM (
= 15) without clinical microvascular disease. We measured insulin's effect on
) skeletal muscle microvascular perfusion using contrast-enhanced ultrasound (CEU),
) arterial stiffness using carotid-femoral pulse-wave velocity (cfPWV) and radial artery pulse wave analysis (PWA), and
) metabolic insulin sensitivity by the glucose infusion rate (GIR) during a 2-h, 1 mU/min/kg euglycemic-insulin clamp. Subjects with T1DM were metabolically insulin resistant (GIR = 5.2 ± 0.7 vs. 6.6 ± 0.6 mg/min/kg,
< 0.001). Insulin increased muscle microvascular blood volume and flow in control (
< 0.001, for each) but not in subjects with T1DM. Metabolic insulin sensitivity correlated with increases of muscle microvascular perfused volume (
< 0.05). Baseline measures of vascular stiffness did not differ between groups. However, during hyperinsulinemia, cfPWV was greater (
< 0.02) in the T1DM group and the backward pulse wave pressure declined with insulin only in controls (
< 0.03), both indices indicating that insulin-induced vascular relaxation in controls only. Subjects with T1DM have muscle microvascular insulin resistance that may precede clinical microvascular disease.
Using contrast ultrasound and measures of vascular stiffness, we compared vascular and metabolic responses to insulin in patients with type 1 diabetes with age-matched controls. The patients with type 1 diabetes demonstrated both vascular and metabolic insulin resistance with more than half of the patients with diabetes having a paradoxical vasoconstrictive vascular response to insulin.
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 age-matched controls at baseline and during an oral glucose challenge (OGTT). DM1 adolescents (
= 16) and controls (
= 14) were studied before and during an OGTT. At baseline, we measured:
) large artery stiffness using both aortic augmentation index (AI) and carotid-femoral pulse wave velocity (cfPWV);
) brachial flow-mediated dilation (FMD) and forearm endothelial function using postischemic flow velocity (PIFV); and
) 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
tests or repeated measures ANOVA. Baseline FMD was lower (
= 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 (
= 0.02) and was lower than DM1 at 60 min (
< 0.03). Baseline MBV was comparable in DM1 and control groups, but declined in DM1 at 120 min (
= 0.01) and was lower than the control group (
< 0.03). There was an inverse correlation between plasma glucose and MBV at 120 min (
= -0.523,
< 0.01). No differences were noted between groups for V̇O
(mL/min/kg), body fat (%), or body mass index (BMI). 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.
This is the first study to show that type 1 diabetes impairs multiple nitric oxide-dependent vascular functions.
Spot 14 (S14) is a protein that is abundantly expressed in lipogenic tissues and is regulated in a manner similar to other enzymes involved in fatty acid synthesis. Deletion of S14 in mice decreased ...lipid synthesis in lactating mammary tissue, but the mechanism of S14’s action is unknown. Here we present the crystal structure of S14 to 2.65 Å and biochemical data showing that S14 can form heterodimers with MIG12. MIG12 modulates fatty acid synthesis by inducing the polymerization and activity of acetyl-CoA carboxylase, the first committed enzymatic reaction in the fatty acid synthesis pathway. Coexpression of S14 and MIG12 leads to heterodimers and reduced acetyl-CoA carboxylase polymerization and activity. The structure of S14 suggests a mechanism whereby heterodimer formation with MIG12 attenuates the ability of MIG12 to activate ACC.
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