Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factor α , interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome's definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.

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A Comprehensive Review on Metabolic Syndrome

Obesity and the risk of heart failure

Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.

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Cardiovascular actions of insulin.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia due to lack of or resistance to insulin. Patients with DM are frequently afflicted with ischemic vascular disease or wound healing defect. It is well known that type 2 DM causes amplification of the atherosclerotic process, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. These complications ultimately lead to impairment of neovascularization and diabetic wound healing. Therapeutic angiogenesis remains an attractive treatment modality for chronic ischemic disorders including PAD and/or diabetic wound healing. Many experimental studies have identified better approaches for diabetic cardiovascular complications, however, successful clinical translation has been limited possibly due to the narrow therapeutic targets of these agents or the lack of rigorous evaluation of pathology and therapeutic mechanisms in experimental models of disease. This paper discusses the current body of evidence identifying endothelial dysfunction and impaired angiogenesis during diabetes.

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Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing.

Cardiovascular disease is a major complication of diabetes mellitus, and improved strategies for prevention and treatment are needed. Endothelial dysfunction contributes to the pathogenesis and clinical expression of atherosclerosis in diabetes mellitus. This article reviews the evidence linking endothelial dysfunction to human diabetes mellitus and experimental studies that investigated the responsible mechanisms. We then discuss the implications of these studies for current management and for new approaches for the prevention and treatment of cardiovascular disease in patients with diabetes mellitus.

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Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications

OBJECTIVE—Endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetic subjects. Metformin is commonly used in the treatment of type 2 diabetes and has known vasculoprotective effects beyond its hypoglycemic ones. We aimed to investigate the vascular effects of metformin in first-degree relatives with metabolic syndrome of type 2 diabetic patients. RESEARCH DESIGN AND METHODS—The study included 31 subjects (age 38.3 ± 7.6 years and BMI 36.3 ± 5.2 kg/m2), who were first-degree relatives of type 2 diabetic patients and who had metabolic syndrome and normal glucose tolerance. The subjects were randomly assigned 1:1 in a double-blind fashion to receive placebo (n = 15) or metformin (n = 16). Endothelial function was assessed by venous occlusion plethysmography, measuring forearm blood flow (FBF) and vascular resistance responses to three intra-arterial infusions of endothelium-dependent (acetylcholine 7.5, 15, and 30 μg/min) and independent (sodium nitroprusside 2, 4, and 8 μg/min) vasodilators. Weight, BMI, systolic and diastolic blood pressure, waist, and laboratory parameters (lipid profile and fasting plasma glucose [FPG]) were assessed at baseline and after treatment. RESULTS—The metformin and placebo groups did not differ in anthropometric, clinical, laboratory, and vascular measurements at baseline. The metformin group had decreased weight, BMI, systolic blood pressure, and FPG and improved lipid profile. Endothelium-dependent FBF responses were also improved, without any effect on endothelium-independent responses. There was no correlation between the improvement on FBF responses and the observed changes on anthropometric, clinical, and laboratory parameters. CONCLUSIONS—We concluded that metformin improved vascular endothelial reactivity in first-degree relatives with metabolic syndrome of type 2 diabetic patients, independently of its known antihyperglycemic effects.

https://care.diabetesjournals.org/content/diacare/29/5/1083.full.pdf

Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance

The role of microcirculatory dysfunction (MD) in metabolic and cardiovascular diseases is not well established. Considering that metabolic syndrome (MS) is an independent risk factor and diabetic patients have microangiopathy, our aim was to investigate if normoglycemic subjects with MS already have detectable skin MD. Thirty-six subjects with MS (National Cholesterol Education Program-Adult Treatment Panel III criteria) (10 men/26 women, 38.8 +/- 7.9 years, 35.8 +/- 4.9 kg/m(2)) with normal glucose tolerance (American Diabetes Association criteria) and 16 controls (11 men/5 women, 33.6 +/- 8.4 years, 23.9 +/- 3.6 kg/m(2)) were studied using nailfold videocapillaroscopy. Afferent, efferent, and apical capillary diameters; functional capillary density; red blood cell velocity (RBCV) at baseline; and RBCV(max) and time (TRBCV(max)) to reach it during postocclusive reactive hyperemia after 1-minute arterial occlusion were measured. Subjects with MS had smaller afferent, efferent, and apical diameters (4.2 [3.8-4.2] vs 5.6 [4.65-6.25] mum, P < .001; 4.8 [4.2-4.8] vs 6.2 [5.6-7] mum, P < .001; and 5.2 [4.8-5.55] vs 7.4 [6.2-8] mum, P < .001); lower functional capillary density (7.28 [6.37-9.10] vs 10.4 [9.1-11.8] capillaries per square millimeter, P < .001), RBCV (0.62 [0.57-0.65] vs 0.79 [0.76-0.89] mm/s, P < .001], and RBCV(max) (1.14 [1.12-1.210] vs 1.57 [1.45-1.62] mm/s, P < .001); and longer TRBCV(max) (10.0 [10-11] vs 4.5 [4-6] seconds, P < .001) compared with controls. Microcirculatory dysfunction was associated with body mass index. We concluded that subjects with MS already have nutritive skin MD even within the normoglycemic milieu.

Skin microcirculatory dysfunction is already present in normoglycemic subjects with metabolic syndrome

Aims Insulin resistance and a parental history of diabetes mellitus are independently associated with endothelial dysfunction. Oxidative stress has a pivotal role in the pathophysiology of vascular injury. Metformin, in addition to its glucose-lowering properties, has vasculoprotective effects. We investigated whether metformin has beneficial effects on the nutritive skin capillary circulation and deceases oxidative stress in a group at high risk for Type 2 diabetes mellitus (T2DM) and cardiovascular disease.



Methods  Thirty normoglycaemic subjects with the metabolic syndrome (MS), who had first-degree relatives with T2DM, participated. The mean age was 39.1 ± 8.4 years and body mass index (BMI) 35.7 ± 4.8 kg/m2 (mean ±sd). Subjects were randomized 1 : 1 to receive placebo (n = 14) or metformin (n = 16; 1700 mg/day) in a double-blind study. At baseline and post treatment, blood and urine samples were collected for biochemical and 8-epi-prostaglandin F2α (8-epi-PGF2α) analysis, respectively. Microcirculation was assessed by nailfold videocapillaroscopy, analysing afferent (AF), efferent (EF) and apical (AP) diameters of capillary loops, functional capillary density (FCD), red blood cell velocity at rest (RBCV), after 1 min arterial occlusion (RBCVmax) and time (TRBCVmax) taken to reach it.



Results  Groups did not differ significantly in anthropometric, clinical, laboratory or microvascular measurements at baseline. In the metformin group, weight, BMI, systolic blood pressure and fasting plasma glucose fell, and lipid profile and microcirculatory parameters FCD, AF, EF, AP, RBCVmax and TRBCVmax improved (all P < 0.01). No relationship between clinico-laboratory parameters and microvascular reactivity was observed, except for changes in total and low-density lipoprotein-cholesterol and RBCVmax. 8-epi-PGF2α did not change significantly in either group.



Conclusions  Metformin improved skin capillary reactivity in normoglycaemic MS subjects independently of significant changes in 8-epi-PGF2α levels.

Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome

Ischemia/reperfusion (I/R) injury can occur in consequence of myocardial infarction, stroke and multiple organ failure, the most prevalent cause of death in critically ill patients. I/R injury encompass impairment of endothelial dependent relaxation, increase in macromolecular permeability and leukocyte-endothelium interactions. Polyunsaturated fatty acids (n-3 PUFA), such as eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) found in fish oil have several anti-inflammatory properties and their potential benefits against I/R injury were investigated using the hamster cheek pouch preparation before and after ischemia. Before the experiments, hamsters were treated orally with saline, olive oil, fish oil and triacylglycerol (TAG) and ethyl ester (EE) forms of EPA and DHA at different daily doses for 14 days. Fish oil restored the arteriolar diameter to pre ischemic values during reperfusion. At onset and during reperfusion, Fish oil and DHA TAG significantly reduced the number of rolling leukocytes compared to saline and olive oil treatments. Fish oil, EPA TAG and DHA TAG significantly prevented the rise on leukocyte adhesion compared to saline. Fish oil (44.83 ± 3.02 leaks/cm2), EPA TAG (31.67 ± 2.65 leaks/cm2), DHA TAG (41.14 ± 3.63 leaks/cm2), and EPA EE (30.63 ± 2.25 leaks/cm2), but not DHA EE (73.17 ± 2.82 leaks/cm2) prevented the increase in macromolecular permeability compared to saline and olive oil (134.80 ± 1.49 and 121.00 ± 4.93 leaks/cm2, respectively). On the basis of our findings, we may conclude that consumption of n-3 polyunsaturated fatty acids, especially in the triacylglycerol form, could be a promising therapy to prevent microvascular damage induced by ischemia/reperfusion and its consequent clinical sequelae.

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n-3 PUFA induce microvascular protective changes during ischemia/reperfusion.

WSTĘP. Insulinoopornośc i rodzinne wystepowanie
cukrzycy niezaleznie wiązą sie z dysfunkcją środblonka.
Stres oksydacyjny odgrywa kluczową role w patofizjologii
uszkodzenia naczyn krwionośnych. Metformina,
oprocz obnizania stezenia glukozy, dziala
ochronnie na naczynia. Celem niniejszej pracy by³o
zbadanie, czy metformina korzystnie wplywa na krązenie w odzywczych naczyniach wlosowatych skory
oraz czy zmniejsza stres oksydacyjny u osob wysokiego
ryzyka wystąpienia cukrzycy typu 2 i chorob
sercowo-naczyniowych.
 METODY. Badaniem objeto 30 pacjentow z prawidlowym
stezeniem glukozy i zespolem metabolicznym
(MS), ktorzy mieli krewnych chorych na cukrzyce typu
2. średni wiek wynosil 39,1 ± 8,4 roku, a wskaźnik
masy ciala (BMI) 35,8 ± 4,8 kg/m 2 (średnia ± odchylenie
standardowe). Pacjentow losowo podzielono
na 2 grupy za pomocą metody podwojnie lepej proby w stosunku 1:1 - 14 osob otrzymywalo placebo,
a 16 metformine (1700 mg/d.). Wyjściowo
i po zakonczeniu badania pobrano krew do analizy
biochemicznej oraz mocz w celu określenia stezenia
8-epi-prostaglandyny F 2α (8-epi-PGF 2α ). Krązenie
w naczyniach wlosowatych oceniano za pomocą wideokapilaroskopii
obrąbka naskorkowego, podczas
ktorej analizowano średnice petli naczyn wlosowatych
doprowadzających (AF), odprowadzających (EF)
i wierzcholkowych (AP), funkcjonalną gestośc naczyn
wlosowatych (FCD), predkośc przeplywu czerwonych
cialek krwi w spoczynku (RBCV) oraz po 1 minucie
od okluzji naczyn tetniczych (RBCV max ), a takze czas
potrzebny do jej osiągniecia (TRBCV max ).
 WNIOSKI. Metformina poprawila reaktywnośc naczyn wlosowatych skory u osob z prawidlową glikemią i zespolem metabolicznym, niezaleznie od zmian
stezenia 8-epi-PGF 2α .

C.M. Laflor

Papers

Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance

Skin microcirculatory dysfunction is already present in normoglycemic subjects with metabolic syndrome

Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome

n-3 PUFA induce microvascular protective changes during ischemia/reperfusion.

Metformin improves skin capillary reactivity in normoglycaemic subjects with the metabolic syndrome