The metabolic syndrome

The universality of calcium as an intracellular messenger depends on its enormous versatility. Cells have a calcium signalling toolkit with many components that can be mixed and matched to create a wide range of spatial and temporal signals. This versatility is exploited to control processes as diverse as fertilization, proliferation, development, learning and memory, contraction and secretion, and must be accomplished within the context of calcium being highly toxic. Exceeding its normal spatial and temporal boundaries can result in cell death through both necrosis and apoptosis.

The versatility and universality of calcium signalling

White adipose tissue is no longer considered an inert tissue mainly devoted to energy storage but is emerging as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Furthermore, cross-talk between lymphocytes and adipocytes can lead to immune regulation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines leptin, adiponectin, resistin, and visfatin, as well as cytokines and chemokines, such as TNF-α, IL-6, monocyte chemoattractant protein 1, and others. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified.

https://www.jacionline.org/article/S0091-6749(05)00417-3/pdf

Adipose tissue, adipokines, and inflammation.

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

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From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Diabetes mellitus affects approximately 100 million persons worldwide.1 Five to ten percent have type 1 (formerly known as insulin-dependent) and 90% to 95% have type 2 (non–insulin-dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns contributing to obesity.2 Cardiovascular physicians are encountering many of these patients because vascular diseases are the principal causes of death and disability in people with diabetes. The macrovascular manifestations include atherosclerosis and medial calcification. The microvascular consequences, retinopathy and nephropathy, are major causes of blindness and end-stage renal failure. Physicians must be cognizant of the salient features of diabetic vascular disease in order to treat these patients most effectively. The present review will focus on the relationship of diabetes mellitus and atherosclerotic vascular disease, highlighting pathophysiology and molecular mechanisms (Part I) and clinical manifestations and management strategies (Part II).

Abnormalities in endothelial and vascular smooth muscle cell function, as well as a propensity to thrombosis, contribute to atherosclerosis and its complications. Endothelial cells, because of their strategic anatomic position between the circulating blood and the vessel wall, regulate vascular function and structure. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.3 Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of l-arginine.4 The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.4 In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with …

/pdf/diabetes-and-vascular-disease-pathophysiology-clinical-1bcq6bpu8b.pdf

Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part I

Atherosclerosis is an inflammatory disease that is marked by increased presence of Tumor Necrosis Factor-alpha (TNFα), increased expression of Vascular Cell Adhesion Molecule-1 (VCAM-1), increased presence of serum monocytes and activation of the canonical inflammatory molecule, Nuclear Factor Kappa-B (NFκB). Hyperinsulinemia is a hallmark of insulin resistance and may play a key role in this inflammatory process. Using Western blot analysis, immunocytochemistry, flow cytometry and biochemical inhibitors, we measured changes in VCAM-1 protein expression and NFκB translocation in vascular endothelial cells in the presence of TNFα and/or hyperinsulinemia and in the absence or presence of kinase pathway inhibitors. We report that hyperinsulinemia augmented TNFα stimulated increases in VCAM-1 protein greater than seen with TNFα alone and decreased the time in which VCAM-1 translocated to the cell surface. We also observed that in the presence of Wortmannin, a biochemical inhibitor of phosphatidylinositol 3-kinase (a hallmark of insulin resistance), VCAM-1 expression was greater in the presence of TNFα plus insulin as compared to that seen with insulin or TNFα alone. Additionally, nuclear import of NFκB occurred sooner in the presence of insulin and TNFα together as compared to each alone, and in the presence of Wortmannin, nuclear import of NFκB was greater than that seen with insulin and TNFα alone. hyperinsulinemia and insulin resistance appear to augment the inflammatory effects of TNFα on VCAM-1 expression and NFκB translocation, both of which are markers of inflammation in the vasculature.

/pdf/insulin-augments-tumor-necrosis-factor-alpha-stimulated-4zpdt5g7u6.pdf

Insulin augments tumor necrosis factor-alpha stimulated expression of vascular cell adhesion molecule-1 in vascular endothelial cells.

Background

Atherosclerosis may be stimulated by the increased presence of insulin and tumor necrosis-factor-α (TNFα) with subsequent expression of vascular cell adhesion molecule-1 (VCAM-1). We hypothesized that extracellular signal-regulated kinase-5 (ERK5) plays an important role in insulin and TNFα-stimulated total and cell surface VCAM-1 expression.



Methods

Rat aorta vascular endothelial cells were first transfected with either no inhibitory RNA, inactive (scrambled) inhibitory ERK5 RNA (scERK5) or active inhibitory ERK5 RNA (siERK5) and then treated with either (i) no analog; (ii) insulin (1 nM), or TNFα (1 ng/mL) alone, or (iii) insulin plus TNFα for 6 h. Thereafter either total VCAM-1 protein or surface VCAM-1 protein was determined.



Results

Genetic inhibition of ERK5 decreased TNFα-stimulated total VCAM-1 expression by 57% and surface expression by 27%. In contrast, genetic inhibition of ERK5 did not significantly decrease insulin-stimulated total or surface VCAM-1 expression. Interestingly, genetic inhibition of ERK5 did not significantly decrease insulin plus TNFα-stimulated total VCAM-1 expression, but significantly (P < 0.05) decreased insulin plus TNFα-stimulated surface VCAM-1 expression 41%.



Conclusions

We report here that ERK5 plays a minor role in insulin-stimulation of VCAM-1, but plays a significant role in TNFα-stimulation of both total and cell surface VCAM-1 protein expression. Taken together, these results demonstrate that not only does ERK5 have differential mediation of insulin and TNFα-stimulated VCAM-1 expression, but also has differential regulation of insulin plus TNFα-stimulated total and surface VCAM-1 expression, suggesting that other intermediates of the insulin and TNFα intracellular pathways are contributing to atherogenesis.


摘要

背景：胰岛素与肿瘤坏死因子-α（tumor necrosis-factor-α，TNFα）水平升高后可以促进动脉粥样硬化的形成，随后血管细胞粘附分子-1（vascular cell adhesion molecule-1，VCAM-1）的表达也增加。我们假设细胞外信号调节激酶-5（extracellular signal-regulated kinase-5，ERK5）对在胰岛素与TNF-α刺激下的总的以及细胞表面的VCAM-1的表达起着重要的作用。



方法：首先，采用非抑制性RNA，亦即无活性的（乱序的）抑制性ERK5 RNA（scERK5）或活性的抑制性ERK5 RNA（siERK5）对大鼠的主动脉血管内皮细胞进行转染，接着采用(i)没有模拟物，或(ii)单独的胰岛素(1 nM)或TNFα (1 ng/mL)，或(iii)胰岛素加TNFα治疗，共6小时。此后测定总的VCAM-1蛋白或细胞表面的VCAM-1蛋白。



结果：ERK5的基因抑制作用可以使TNFα刺激下的总VCAM-1表达下降57%，使细胞表面的VCAM-1表达下降27%。相比之下，ERK5的基因抑制作用不能够使胰岛素刺激下的总VCAM-1或者细胞表面的VCAM-1表达显著下降。有趣的是，ERK5的基因抑制作用不能够使胰岛素加TNFα刺激下的总VCAM-1表达显著下降，但是能够使胰岛素加TNFα刺激下的细胞表面的VCAM-1表达显著下降41%（P < 0.05）。



结论：我们的报告显示ERK5对胰岛素刺激下的VCAM-1表达影响很小，但是对TNFα刺激下的总的以及细胞表面的VCAM-1蛋白表达的影响都很显著。综上所述，这些结果表明，ERK5不但对胰岛素或TNFα刺激下的VCAM-1表达具有不同的介导作用，而且对胰岛素加TNFα刺激下的总的以及细胞表面的VCAM-1表达也具有不同的调节作用，这提示胰岛素与TNFα的细胞内信号通路的其他中间介质导致了动脉粥样硬化的形成。

Extracellular signal-regulated kinase-5: Novel mediator of insulin and tumor necrosis factor α-stimulated vascular cell adhesion molecule-1 expression in vascular cells 细胞外信号调节激酶-5：一种新的调节胰岛素与肿瘤坏死因子α刺激下的血管细胞上的血管细胞粘附分子-1表达的介质

Dominant negative α-subunit of farnesyl- and geranylgeranyl-transferase I inhibits insulin-induced differentiation of 3T3-L1 pre-adipocytes

Marc L. Goalstone

Papers

Insulin augments tumor necrosis factor-alpha stimulated expression of vascular cell adhesion molecule-1 in vascular endothelial cells.

Dominant negative alpha-subunit of farnesyl- and geranylgeranyl-transferase I inhibits insulin-induced differentiation of 3T3-L1 pre-adipocytes.

GTP Loading of Farnesylated p21Ras by Insulin at the Plasma Membrane

Regulation of ERK5 by insulin and angiotensin-II in vascular smooth muscle cells