Lycopene ameliorates insulin resistance and increases muscle capillary density in aging via activation of SIRT1

Abstract Context: Low birth weight (LBW), a surrogate marker of an adverse fetal milieu, is linked to muscle insulin resistance, impaired insulin-stimulated glycolysis, and future risk of type 2 diabetes. Skeletal muscle mass, fiber composition, and capillary density are important determinants of muscle function and metabolism, and alterations have been implicated in the pathogenesis of insulin resistance. Objective: The aim of this study was to investigate whether an adverse fetal environment (LBW) induces permanent changes in skeletal muscle morphology, which may contribute to the dysmetabolic phenotype associated with LBW. Design and Subjects: Vastus lateralis muscle was obtained by percutaneous biopsy from 20 healthy 19-yr-old men with birth weights at 10th percentile or lower for gestational age (LBW) and 20 normal birth weight controls, matched for body fat, physical fitness, and whole-body glucose disposal. Myofibrillar ATPase staining was used to classify muscle fibers as type I, IIa, and IIx (formerly type IIb), and double immunostaining was performed to stain capillaries (LBW, n = 8; normal birth weight, n = 12). Results: LBW was associated with increased proportion of type IIx fibers (+66%; P = 0.03), at the expense of decreased type IIa fibers (−22%; P = 0.003). No significant change was observed in proportion of type I fibers (+16%; P = 0.11). In addition, mean area of type IIa fibers was increased (+29%; P = 0.01) and tended to be increased for type I fibers as well (+17%; P = 0.08). Capillary density was not significantly different between groups. Conclusion: Alterations in fiber composition and size may contribute to development of type 2 diabetes in individuals with LBW.

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Abstract 402: Human CD271-positive Adipose Derived Stem Cells are the Angiogenic Subset Decreased by Donor Insulin Resistance

Circulation Research ◽

10.1161/res.127.suppl_1.402 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Oto Inoue ◽

Soichiro Usui ◽

Kosei Yamaguchi ◽

Yusuke Takeda ◽

Chiaki Goten ◽

...

Keyword(s):

Insulin Resistance ◽

Stem Cells ◽

Adipose Tissue ◽

Cell Therapy ◽

Capillary Density ◽

Adipose Derived Stem Cells ◽

Knock Out ◽

Healthy Donors ◽

Knock Out Mice

Introduction: Type 2 diabetes mellitus (T2DM) is an important risk factor for cardiovascular diseases (CVDs). Recently, cell therapy using adipose-derived stem cells (ADSCs) has emerged as an attractive therapy for severe CVDs because of their angiogenic potentials. However, whether and how T2DM would impair human ADSC angiogenic capacity is still uncertain. We previously reported that CD31 - CD34 + CD271 + ADSCs (CD271 + ADSCs) were specifically decreased in adipose tissue of T2DM patients. Therefore, we aimed to investigate the angiogenic capacity of CD271 + ADSCs. Furthermore, we evaluate which patients’ parameters regard as T2DM would decrease the amount of CD271 + ADSCs. Methods and Results: Human CD45 - CD34 + CD31 - ADSCs were obtained from subcutaneous adipose tissue of healthy donors, separated into CD271 + and CD271 - subsets by FACS, and cultured. Both subsets of ADSCs were assessed gene expression profile by microarray. Microarray analysis and validation PCR elucidated that PI3K/Akt/mTOR pathway was significantly up-regulated in CD271 + ADSCs compared to in CD271 - ADSCs. ( p < 0.05). Then, we compared in vivo angiogenic capacity in xenograft experiments of nude mice subjected to hindlimb ischemia. Angiogenesis was evaluated histologically using perfused lectin (capillary density) at day 14. Cell therapy using CD271 + ADSCs demonstrated about 3-fold more lectin + capillaries compared to CD271 - ADSCs or PBS injection ( p < 0.005, n = 5 / group). Next, we established cultured ADSCs obtained from CD271 knock-out mice (KO-ADSCs) and compared their angiogenic capacity with those from WT mice. Consistently, KO-ADSCs demonstrated impaired in vivo angiogenic capacity ( p < 0.005, n = 5 / group). Finally, we collected 23 samples of adipose tissue obtained from CVD patients and evaluated the frequency of CD271 + ADSCs in CD45 - CD34 + CD31 - ADSCs. Among studied parameters, HOMA-IR, an index of insulin resistance, was negatively correlated with the frequency of CD271+ ADSCs ( r = -0.64, p < 0.005). Conclusions: Human CD271 + ADSCs demonstrated enhanced in vivo angiogenic capacity with higher mTOR expression. Donor insulin resistance might decrease this regenerative subset of ADSCs. These findings would be critical for development and improvement of ADSC therapy.

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Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00205.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. E640-E648 ◽

Cited By ~ 13

Author(s):

Weidong Chai ◽

Zhuo Fu ◽

Kevin W. Aylor ◽

Eugene J. Barrett ◽

Zhenqi Liu

Keyword(s):

Insulin Resistance ◽

Endothelial Function ◽

High Fat Diet ◽

Capillary Density ◽

Glucose Disposal ◽

Endothelial Cell Proliferation ◽

High Fat ◽

Euglycemic Hyperinsulinemic Clamp ◽

Receptor Agonists ◽

Microvascular Recruitment

Muscle microvasculature critically regulates endothelial exchange surface area to facilitate transendothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.

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Association of Adipokines with Insulin Resistance, Microvascular Dysfunction, and Endothelial Dysfunction in Healthy Young Adults

Mediators of Inflammation ◽

10.1155/2015/594039 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Cynthia Cheng ◽

Constantine Daskalakis

Keyword(s):

Insulin Resistance ◽

Endothelial Dysfunction ◽

Microvascular Dysfunction ◽

Capillary Density ◽

Potential Interaction ◽

Normal Weight ◽

Inflammation Markers ◽

Asymptomatic Individuals ◽

Study Participants ◽

Pai 1

Proinflammatory adipokines (inflammation markers) from visceral adipose tissue may initiate the development of insulin resistance (IR) and endothelial dysfunction (ED). This study’s objective was to investigate the association of five inflammation markers (CRP and four adipokines: IL-6, TNFα, PAI-1, and adiponectin) with IR (quantitative insulin resistance check index (QUICKI)), microvascular measures (capillary density and albumin-to-creatinine ratio (ACR)), and endothelial measures (forearm blood flow (FBF) increases from resting baseline to maximal vasodilation). Analyses were conducted via multiple linear regression. The 295 study participants were between 18 and 45 years of age, without diabetes or hypertension. They included 24% African Americans and 21% Asians with average body mass index of 25.4 kg/m2. All five inflammation markers were significantly associated with QUICKI. All but adiponectin were significantly associated with capillary density, but none were associated with ACR. Finally, IL-6 and PAI-1 were significantly associated with FBF increase. We also identified a potential interaction between obesity and IL-6 among normal-weight and overweight participants: IL-6 appeared to be positively associated with QUICKI and capillary density (beneficial effect), but the inverse was true among obese individuals. These study findings suggest that inflammation measures may be potential early markers of cardiovascular risk in young asymptomatic individuals.

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