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

Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells.

Insulin resistance is concomitant with type 2 diabetes, obesity, hypertension, and other features of the metabolic syndrome. Because insulin resistance is associated with cardiovascular disease, both scientists and physicians have taken great interest in this disorder. Insulin resistance is associated with compensatory hyperinsulinemia, but individual contributions of either of these two conditions remain incompletely understood and a subject of intense investigation. One possibility is that in an attempt to overcome the inhibition within the metabolic insulin-signaling pathway, hyperinsulinemia may continue to stimulate the mitogenic insulin-signaling pathway, thus exerting its detrimental influence. Here we discuss some of the effects of insulin resistance and mechanisms of potentially detrimental influence of hyperinsulinemia in the presence of metabolic insulin resistance.

https://diabetes.diabetesjournals.org/content/diabetes/53/11/2735.full.pdf

Molecular Mechanisms of Insulin Resistance That Impact Cardiovascular Biology

Molecular mechanisms of insulin resistance that impact cardiovascular biology. Perspectives in diabetes

Objective: To determine whether macronutrient composition of a hypocaloric diet can enhance its effectiveness and whether insulin sensitivity (Si) affects the response to hypocaloric diets.



Research Methods and Procedures: Obese nondiabetic insulin-sensitive (fasting insulin 15 μU/mL; n = 9) women (23 to 53 years old) were randomized to either a high carbohydrate (CHO) (HC)/low fat (LF) (60% CHO, 20% fat) or low CHO (LC)/high fat (HF) (40% CHO, 40% fat) hypocaloric diet. Primary outcome measures after a 16-week dietary intervention were: changes in body weight (BW), Si, resting metabolic rate, and fasting lipids.



Results: Insulin-sensitive women on the HC/LF diet lost 13.5 ± 1.2% (p < 0.001) of their initial BW, whereas those on the LC/HF diet lost 6.8 ± 1.2% (p < 0.001; p < 0.002 between the groups). In contrast, among the insulin-resistant women, those on the LC/HF diet lost 13.4 ± 1.3% (p < 0.001) of their initial BW as compared with 8.5 ± 1.4% (p < 0.001) lost by those on the HC/LF diet (p < 0.04 between two groups). These differences could not be explained by changes in resting metabolic rate, activity, or intake. Overall, changes in Si were associated with the degree of weight loss (r = −0.57, p < 0.05).



Discussion: The state of Si determines the effectiveness of macronutrient composition of hypocaloric diets in obese women. For maximal benefit, the macronutrient composition of a hypocaloric diet may need to be adjusted to correspond to the state of Si.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/oby.2005.79

Marc L. Goalstone

Papers

Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells.

Molecular Mechanisms of Insulin Resistance That Impact Cardiovascular Biology

Molecular mechanisms of insulin resistance that impact cardiovascular biology. Perspectives in diabetes

Insulin sensitivity determines the effectiveness of dietary macronutrient composition on weight loss in obese women

Effect of Insulin on Cell Cycle Progression in MCF-7 Breast Cancer Cells: DIRECT AND POTENTIATING INFLUENCE *