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Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

ABSTRACT: Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease, 2) determine whether female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity, and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Finally, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.

SUBMITTER: Manrique-Acevedo C

PROVIDER: S-EPMC9942885 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

Manrique-Acevedo Camila C Soares Rogerio N RN Smith James A JA Park Lauren K LK Burr Katherine K Ramirez-Perez Francisco I FI McMillan Neil J NJ Ferreira-Santos Larissa L Sharma Neekun N Olver T Dylan TD Emter Craig A CA Parks Elizabeth J EJ Limberg Jacqueline K JK Martinez-Lemus Luis A LA Padilla Jaume J

American journal of physiology. Regulatory, integrative and comparative physiology 20230109 3

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to <i>1</i>) establish if sex differenc ...[more]

PMID: 36622084

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Project description:To examine the relationships between plasma and tissue markers of systemic and vascular inflammation and obesity and insulin resistance and determine the effects of aerobic exercise training plus weight loss (AEX+WL) and weight loss (WL) alone on these biomarkers.Prospective controlled study.Veterans Affairs Medical Center and University research setting.Overweight and obese sedentary postmenopausal women (N = 77).Six months, 3 d/wk AEX+WL (n = 37) or WL (n = 40).Total-body dual-energy X-ray absorptiometry, abdominal computed tomography, hyperinsulinemic-euglycemic clamps (a criterion standard method of assessing insulin sensitivity), adipose tissue biopsies (n = 28), and blood for homeostasis model assessment-insulin resistance, and soluble forms of intracellular adhesion molecule 1 (sICAM-1) and vascular cell adhesion molecule 1 (sVCAM-1), C-reactive protein (CRP), and serum amyloid A (SAA).Body weight (P < .001), percentage of fat (P < .001), visceral fat (P < .005), triglyceride levels (P < .001), and systolic blood pressure decreased comparably after WL and AEX+WL (P = .04). Maximal oxygen consumption increased 16% after AEX+WL (P < .001). Insulin resistance decreased in both groups (P = .005). Glucose utilization according to the clamp increased 10% (P = .04) with AEX+WL and 8% with WL (P = .07). AEX+WL decreased CRP by 29% (P < .001) and WL by 21% (P = .02). SAA levels decreased twice as much after AEX+WL (-19%, P = .02) as after WL (-9%, P = .08). Plasma sICAM-1 and sVCAM-1 levels did not change, but women with the greatest reduction in plasma sICAM-1 levels had the greatest reductions in fasting glucose (P = .02), insulin (P = .02), and insulin resistance (P = .004). Gluteal ICAM messenger ribonucleic acid levels decreased 27% after AEX+WL (P = .02) and did not change after WL.Obesity and insulin resistance worsen markers of systemic and vascular inflammation. A reduction in plasma sICAM-1 is important to improve insulin sensitivity. CRP, SAA, and tissue ICAM decrease with exercise and weight loss, suggesting that exercise training is a necessary component of lifestyle modification in obese postmenopausal women.

Project description:BackgroundCardiovascular disease is the leading cause of mortality in type 1 diabetes mellitus (T1DM) and relates strongly to insulin resistance (IR). Lean and obese adolescents with T1DM have marked IR. Metformin improves surrogate markers of IR in T1DM, but its effect on directly measured IR and vascular health in youth with T1DM is unclear. We hypothesized that adolescents with T1DM have impaired vascular function and that metformin improves this IR and vascular dysfunction.MethodsAdolescents with T1DM and control participants underwent magnetic resonance imaging of the ascending (AA) and descending aorta to assess pulse wave velocity, relative area change, and maximal (WSSMAX) and time-averaged (WSSTA) wall shear stress. Participants with T1DM also underwent assessment of carotid intima-media thickness by ultrasound, brachial distensibility by DynaPulse, fat and lean mass by dual-energy x-ray absorptiometry, fasting laboratories after overnight glycemic control, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate/insulin). Adolescents with T1DM were randomized 1:1 to 3 months of 2000 mg metformin or placebo daily, after which baseline measures were repeated.ResultsForty-eight adolescents with T1DM who were 12 to 21 years of age (40% body mass index [BMI] ≥90th percentile; 56% female) and 24 nondiabetic control participants of similar age, BMI, and sex distribution were enrolled. Adolescents with T1DM demonstrated impaired aortic health compared with control participants, including elevated AA and descending aorta pulse wave velocity, reduced AA and descending aorta relative area change, and elevated AA and descending aorta WSSMAX and WSSTA. Adolescents with T1DM in the metformin versus placebo group had improved glucose infusion rate/insulin (12.2±3.2 [mg·kg-1·min-1]/μIU/μL versus -2.4±3.6 [mg·kg-1·min-1]/μIU/μL, P=0.005; 18.6±4.8 [mg·lean kg-1·min-1]/μIU/μL versus -3.4±5.6 [mg·lean kg-1·min-1]/μIU/μL, P=0.005) and reduced weight (-0.5±0.5 kg versus 1.6±0.5 kg; P=0.004), BMI (-0.2±0.15 kg/m2 versus 0.4±0.15 kg/m2; P=0.005), and fat mass (-0.7±0.3 kg versus 0.6±0.4 kg; P=0.01). Glucose infusion rate/insulin also improved in normal-weight participants (11.8±4.4 [mg·kg-1·min-1]/μIU/μL versus -4.5±4.4 [mg·kg-1·min-1]/μIU/μL, P=0.02; 17.6±6.7 [mg·lean kg-1·min-1]/μIU/μL versus -7.0±6.7 [mg·lean kg-1·min-1]/μIU/μL, P=0.02). The metformin group had reduced AA WSSMAX (-0.3±0.4 dyne/cm2 versus 1.5±0.5 dyne/cm2; P=0.03), AA pulse wave velocity (-1.1±1.20 m/s versus 4.1±1.6 m/s; P=0.04), and far-wall diastolic carotid intima-media thickness (-0.04±0.01 mm versus -0.00±0.01 mm; P=0.049) versus placebo.ConclusionsAdolescents with T1DM demonstrate IR and impaired vascular health compared with control participants. Metformin improves IR, regardless of baseline BMI, and BMI, weight, fat mass, insulin dose, and aortic and carotid health in adolescents with T1DM. Metformin may hold promise as a cardioprotective intervention in T1DM.Clinical trial registrationURL: https://www.clinicaltrials.gov . Unique identifier: NCT01808690.

Project description:Dietary calorie restriction and exercise promote weight loss and may have additive effects for improving insulin sensitivity, independent of weight loss. It is not known if these effects are attributable to changes in circulating cytokines. We evaluated the hypothesis that modest, matched weight loss induced by calorie restriction and exercise have additive effects on circulating cytokines and these changes correlate with improvements in insulin sensitivity. Overweight and sedentary women and men (n?=?52, 45-65 years) were randomized to undergo 7?% weight loss by using 3-6 months of calorie restriction, exercise, or a combination of both calorie restriction and exercise. Concentrations of cytokines and hormones were measured in fasting and oral glucose tolerance test blood samples. Insulin sensitivity was estimated based on oral glucose tolerance test for glucose and insulin. With all groups combined, fasting leptin (p?<?0.0001) and high molecular weight adiponectin (p?=?0.04) decreased and pentraxin-3 increased (p?<?0.0001), in a manner that correlated with improvements in insulin sensitivity (all p???0.0002). These changes, combined with decreases in glucose-dependent insulinotropic polypeptide from the oral glucose tolerance test, explained 63?% of the variance (p?<?0.0001) in insulin sensitivity improvements. Exercise and calorie restriction had additive effects on leptin, with a similar trend for high molecular weight adiponectin. Monocyte chemoattractant protein-1 and C-reactive protein concentrations did not change. Calorie restriction and exercise had opposite effects on soluble tumor necrosis factor receptor-1. Modest weight loss in overweight adults decreases serum leptin and high molecular weight adiponectin, and increases pentraxin-3 concentrations in a manner that correlates with increased insulin sensitivity. Exercise has additive effects to those induced by calorie restriction for reductions in leptin and possibly adiponectin. These changes may contribute to the additive effects of calorie restriction and exercise for improving insulin sensitivity.

Project description:BackgroundWeight gain is associated with deterioration in metabolic health, whereas weight loss improves insulin sensitivity. This study assesses the impact of long-term, successfully maintained weight loss and weight-loss relapse on measures of insulin sensitivity and identifies factors that explain variability in insulin sensitivity.MethodsWomen (20-45 years) were recruited into four groups: reduced-overweight/obese (RED, n=15); body mass index (BMI)-matched controls (stable low-weight, n=19), BMI?27?kg?m-2; relapsed-overweight/obese subjects (REL, n=11); and BMI-matched controls (obese stable weight, n=11), BMI?27?kg?m-2. A 75?g oral glucose tolerance test determined fasting and 2?h plasma glucose and insulin. Homeostatic Model Assessment (HOMA-IR) and insulin sensitivity index (ISI(0,120)) assessed insulin sensitivity. Anthropometric measurements, fasting resting metabolic rate (RMR) and respiratory quotient (RQ) were measured. Questionnaires and dietary intake were recorded, and physical activity was measured using accelerometers.ResultsRED were more insulin sensitive, characterised by lower fasting (P=0.001) and 2?h insulin (P=0.003) levels compared with all other groups. There were no significant differences in dietary intake, sedentary, light and moderate activity, RMR or RQ in the RED compared with the other three groups. % Body weight (BW) lost (P<0.001), % BW regained (P<0.05), body fat %, light activity (P<0.05, only log HOMA), vigorous activity (P<0.05) and RQ (P<0.01) predicted 61.4% and 59.7% of variability in log HOMA and log ISI(0,120), respectively, in multiple linear regression models.ConclusionThis study showed sustained enhanced insulin sensitivity in successful weight loss maintainers compared with BMI-matched controls with no weight loss history. Weight-loss-relapsed individuals were indistinguishable from controls. Weight loss itself was the strongest predictor of improved insulin sensitivity, whereas weight regain significantly predicted reduced insulin sensitivity. Weight-loss maintenance programs are essential to retaining metabolic benefits acquired through weight loss. Being physically active, reducing sedentary behaviour and, in particular, including small amounts of vigorous physical activity significantly predicted improved insulin sensitivity.

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Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

Publications

Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

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