Impact of Insulin-Induced Relative Hypoglycemia on Vascular Insulin Sensitivity and Central Hemodynamics in Prediabetes.

CONTEXT: Relative hypoglycemia (RH) is linked to sympathetic responses that can alter vascular function in individuals with type 2 diabetes. However, less is known about the role of RH on hemodynamics or metabolic insulin sensitivity in prediabetes. OBJECTIVE: Determine if RH alters peripheral endothelial function or central hemodynamics to a greater extent in those with prediabetes (PD) versus normoglycemia (NG). METHODS: Seventy adults with obesity were classified using ADA criteria as PD (n=34 (28F); HbA1c=6.02±0.1%) or NG (n=36 (30F); HbA1c=5.4±0.0%). Brachial artery endothelial function, skeletal muscle capillary perfusion, and aortic waveforms were assessed at 0 and 120min of a euglycemic clamp (40 mU/m2/min, 90 mg/dl). Plasma nitrate/nitrite and endothelin-1 (ET-1) were measured as surrogates of nitric oxide-mediated vasodilation and vasoconstriction, respectively. RH was defined as the drop in glucose (%) from fasting to clamp steady state. RESULTS: There were no differences in age, weight, or VO2max between groups. PD had higher HbA1c (P<0.01) and a greater drop in glucose in response to insulin (14 vs. 8%; P=0.03). Further, heart rate (HR) increased in NG compared to PD (P<0.01), while forward wave (Pf) decreased in PD (P=0.04). Insulin also tended to reduce arterial stiffness (cfPWV) in NG versus PD (P=0.07), despite similar increases in pre-occlusion diameter (P=0.02), blood flow (P=0.02), and lower augmentation index (AIx75) (P≤0.05). CONCLUSION: Compared with NG, insulin-induced RH corresponded with a blunted rise in HR and drop in Pf during insulin infusion in adults with PD, independent of changes in peripheral endothelial function.

Intermediate versus morning chronotype has lower vascular insulin sensitivity in adults with obesity.

AIM: Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN). MATERIALS AND METHODS: Adults with obesity were classified per Morningness-Eveningness Questionnaire (MEQ) as either MORN (n = 27, 22 female, MEQ = 63.7 ± 4.7, 53.8 ± 6.7 years, 35.3 ± 4.9 kg/m2) or INT (n = 29, 23 female, MEQ = 48.8 ± 6.7, 56.6 ± 9.0 years, 35.7 ± 6.1 kg/m2). A 120 min euglycaemic-hyperinsulinaemic clamp (40 mU/m2/min, 90 mg/dl) was conducted to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation (%FMD; conduit artery), post-ischaemic flow velocity (resistance arteriole), as well as microvascular insulin sensitivity via contrast-enhanced ultrasound [e.g. microvascular blood volume (perfusion)]. Fasting plasma arginine and citrulline, as well as fasting and clamp-derived plasma endothelin-1 and nitrate/nitrite, were assessed as surrogates of vasoconstriction and nitric oxide-mediated vasodilation. Aerobic fitness (VO2max) and body composition (dual-energy X-ray absorptiometry) were also collected. RESULTS: MORN had a higher VO2max compared with INT (p < .01), although there was no difference in fat mass. While fasting FMD was similar between groups, insulin lowered FMD corrected to shear stress and microvascular blood volume in INT compared with MORN after co-varying for VO2max (both p ≤ .02). INT also had a lower fasting nitrate (p = .03) and arginine (p = .07). Higher MEQ correlated with elevated FMD (r = 0.33, p = .03) and lower post-ischaemic flow velocity (r = -0.33, p = .03) as well as shear rate (r = -0.36, p = .02) at 120 min. CONCLUSION: When measured during the morning, INT had a lower vascular insulin sensitivity than MORN. Additional work is needed to understand endothelial function differences among chronotypes to optimize cardiovascular disease risk reduction.

Impact of Caloric Restriction and Exercise on Trimethylamine N-Oxide Metabolism in Women with Obesity.

Trimethylamine N-oxide (TMAO) is linked to cardiovascular disease (CVD) through partly altered central hemodynamics. We sought to examine if a low-calorie diet plus interval exercise (LCD+INT) intervention reduces TMAO more than a low-calorie diet (LCD) program alone in relation to hemodynamics, prior to clinically meaningful weight loss. Women with obesity were randomized to 2 weeks of LCD (n = 12, ~1200 kcal/d) or LCD+INT (n = 11; 60 min/d, 3 min at 90% and 50% HRpeak, respectively). A 180 min 75 g OGTT was performed to assess fasting TMAO and precursors (carnitine, choline, betaine, and trimethylamine (TMA)) as well as insulin sensitivity. Pulse wave analysis (applanation tonometry) including augmentation index (AIx75), pulse pressure amplification (PPA), forward (Pf) and backward pressure (Pb) waveforms, and reflection magnitude (RM) at 0, 60, 120, and 180 min was also analyzed. LCD and LCD+INT comparably reduced weight (p < 0.01), fasting glucose (p = 0.05), insulin tAUC180min (p < 0.01), choline (p < 0.01), and Pf (p = 0.04). Only LCD+INT increased VO2peak (p = 0.03). Despite no overall treatment effect, a high baseline TMAO was associated with decreased TMAO (r = -0.45, p = 0.03). Reduced TMAO was related to increased fasting PPA (r = -0.48, p = 0.03). Lowered TMA and carnitine correlated with higher fasting RM (r = -0.64 and r = -0.59, both p < 0.01) and reduced 120 min Pf (both, r = 0.68, p < 0.01). Overall, treatments did not lower TMAO. Yet, people with high TMAO pre-treatment reduced TMAO after LCD, with and without INT, in relation to aortic waveforms.

Relation of Aortic Waveforms with Gut Hormones following Continuous and Interval Exercise among Older Adults with Prediabetes.

Prediabetes raises cardiovascular disease risk, in part through elevated aortic waveforms. While insulin is a vasodilatory hormone, the gut hormone relation to aortic waveforms is less clear. We hypothesized that exercise, independent of intensity, would favor aortic waveforms in relation to gut hormones. Older adults (61.3 ± 1.5 yr; 33.2 ± 1.1 kg/m2) with prediabetes (ADA criteria) were randomized to undertake 60 min of work-matched continuous (CONT, n = 14) or interval (INT, n = 14) exercise for 2 wks. During a 180 min 75-g OGTT, a number of aortic waveforms (applanation tonometry) were assessed: the augmentation pressure (AP) and index (AIx75), brachial (bBP) and central blood pressure (cBP), pulse pressure (bPP and cPP), pulse pressure amplification (PPA), and forward (Pf) and backward pressure (Pb) waveforms. Acylated-ghrelin (AG), des-acylated ghrelin (dAG), GIP, and GLP-1active were measured, and correlations were co-varied for insulin. Independent of intensity, exercise increased VO2peak (p = 0.01) and PPA120min (p = 0.01) and reduced weight (p < 0.01), as well as AP120min (p = 0.02) and AIx75120min (p < 0.01). CONT lowered bSBP (p < 0.02) and bDBP (p < 0.02) tAUC180min more than INT. There were decreases dAG0min related to Pb120min (r = 0.47, p = 0.03), cPP120min (r = 0.48, p = 0.02), and AP120min (r = 0.46, p = 0.02). Declines in AG tAUC60min correlated with lower Pb120min (r = 0.47, p = 0.03) and cPP120min (r = 0.49, p = 0.02) were also found. GLP-1active 0min was reduced associated with lowered AP180min (r = 0.49, p = 0.02). Thus, while CONT exercise favored blood pressure, both intensities of exercise improved aortic waveforms in relation to gut hormones after controlling for insulin.