Microcirculation and Insulin Resistance

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Microcirculation is an « invisible » world, representing billions of smallest vessels and about 500m2 endothelium, the largest endocrine organ in human body. It is organized in a fractal fashion, in essentially three vessel subtypes: mid-and small sized arterioles (regulating vascular resistance), capillaries (<10µm) and venules which collect blood from tissues. Microvessel structure, effector mechanisms and their regulation are strictly adapted to function and fundamental differences exist between the microvessel segments, as well as between the microvascular and the macrovascular beds. This chapter aims at giving to the unaware reader a short but complete overview of these specificities for a better understanding of forthcoming chapters, which are devoted to describe our concept, namely that microcirculatory defects, eventually appearing very early in life, can cause and/or aggravate insulin resistance leading to diabetes and cardiovascular diseases some decades later.

Obesity and insulin resistance show increasing incidence in all ages, especially but not only, in western countries. The world epidemic on obesity imposes a higher prevalence of subjects with insulin resistance. This latter condition is associated with impairments on macro and microvascular function of different degrees. The exact interrelationship and meaning of this association and subsequent result on glucose homeostasis, vascular damage and end-organ impairments deserve further investigations. Techniques used to study the microcirculation could help researchers to clarify these questions. This chapter will focus on techniques employed in humans to investigate the microcirculation, endothelial reactivity, their significance and importance for the understanding of microcirculatory function with special focus on those employed and experienced by the authors.

The increasing incidence and prevalence of insulin resistance and its associated co-morbidities represents a growing concern to public health policy across developed economies world wide. While the economic and psycho-social implications of insulin resistance and the ultimate development of type II diabetes mellitus are profound, much of this is associated with the increased probability of afflicted individuals for the development of peripheral vascular disease; with the hallmark characteristics of impaired matching of skeletal muscle perfusion with elevated metabolic demand. Two models of insulin resistance are highlighted in this chapter: the fructose-fed rodent model (which develops insulin resistance in the absence of obesity) and the obese Zucker rat (which develops insulin resistance subsequent to a chronic hyperphagia). While this chapter provides an overview of some of the skeletal muscle perfusion impairments associated with insulin resistance and its satellite co-morbidities, it also provides a discussion of key contributing elements to this relative ischemic condition. Specifically, this chapter will discuss the contributions of altered vascular reactivity from the perspective of both dilator and constrictor responses, the impact of insulin resistance on potassium channel function, structural alterations to microvascular networks (microvascular rarefaction), and the impact of insulin resistance on patterns of capillary recruitment. What rapidly becomes apparent is that the profound impact of pathological states such as insulin resistance on skeletal muscle perfusion represents a spatially and temporally distributed outcome with many contributors resulting in an integrated negative outcome.

The intertwined epidemics of obesity and related disorders such as hypertension, insulin resistance, type 2 diabetes, and subsequent cardiovascular disease pose a major public health challenge. To meet this challenge, we must understand the interplay between adipose tissue and the vasculature. Microvascular dysfunction is important not only in the development of obesityrelated target-organ damage, but also in the development of cardiovascular risk factors such as hypertension and insulin resistance. The present chapter examines the role of microvascular dysfunction as an explanation for the associations among obesity, hypertension and impaired insulin-mediated glucose disposal. We also discuss communicative pathways from adipose tissue to the microcirculation.

Obesity is likely to become a major worldwide epidemic in the 21st century. Clinical evidence demonstrates exaggerated inflammatory responses and an enhanced tissue injury in obese subjects with cardiovascular disease, sepsis, thrombosis and allergic diseases. Emerging evidence suggests that obesity per se is associated with a systemic inflammatory response that is characterized by endothelial cell dysfunction, oxidative stress, and the activation of circulating immune cells. A large number of cytokine-like substances (adipokines) produced by adipose tissue have been implicated in the systemic inflammatory response associated with obesity. Insulin resistance also appears to contribute to the inflammatory phenotype observed in obesity. There is emerging evidence from experimental and clinical studies that implicate the microvasculature as a major target for the deleterious effects of obesity-induced inflammation, and that the altered microvascular responses underlie the exaggerated injury responses to cardiovascular disease, sepsis, thrombosis and allergic diseases in obese subjects.

It became evident in the last years that an increased vascular risk is not only associated with frank diabetes, but also already with states of insulin resistance. This risk does not only affect the large vessels contributing to the augmented cardiovascular risk often observed in insulin resistant patients, but also various functions of the microvasculature. Here we present some evidence that insulin resistant states are clearly associated with an increased formation of reactive oxygen species (ROS) and linked to a state often called “oxidative stress”. Various mechanisms (NADPH-oxidase, disturbed mitochondrial function, uncoupling of nitric oxide synthase) may contribute to oxidative stress, but may also aggravate insulin resistance. It is discussed whether both oxidative stress and insulin resistance are causally linked and why oxidative stress leads to various defects of microvascular function (changes in vasomotion, permeability, reduced capillary bed, induction of apoptosis, changes in gene expression by activation of transcription factors (NFkappB, AP-1, STAT).

The glomerular barrier is highly selective and an only minute amount reaches the urine. Normally, the daily loss of albumin in urine is less than 30 mg and microalbuminuria denotes losses between 30-300 mg per day. Overt proteinuria means daily losses between 300- 3000 mg, whereas larger albumin losses are in the nephrotic range. There are a wide variety of conditions that cause microalbuminuria or proteinuria, but recently our understanding of these phenomena has improved considerably. Microalbuminuria is one of the first signs of diabetic nephropathy where it reflects endothelial dysfunction and increased risk of microvascular complications. Microalbuminuria is also an independent predictor of cardiovascular disease in non-diabetic individuals. Insulin resistance is an interesting condition that precedes the development of type II diabetes. Patients with severe kidney disease have insulin resistance without developing diabetes. Insulin resistance is also associated to microalbuminuria, hypertension and obesity. Finally, there is an association between all these conditions and certain inflammatory vascular reactions. In this chapter, I will try to review our current understanding of microalbuminuria and how it is related to insulin resistance.

Although generation of microparticles from stimulated cells is a universal event of the cell life, little is known about the mechanisms regulating this process. Only in the last ten years, microparticles are considered as vectors of biological information between cells. Levels of circulating microparticles are enhanced in a large number of cardiovascular pathologies including changes in the microcirculation associated with insulino-resistance and this has been associated with deleterious effects on cells from vascular wall, mainly, endothelial cells. However, under several conditions, microparticles released from different vascular cells can induce beneficial effects, such as repair of injured tissue favoring angiogenesis, release of nitric oxide from injured endothelium, for instance. This review emphasizes the increasing significance of microparticles in major cardiovascular pathological situations, as well as, the recent progress in the identification of other biological functions for microparticles, mainly, considering microparticles as potential therapeutic tools.

The insulin resistance syndrome is associated with hemorheologic abnormalities whose understanding is complex, since rheological properties of plasma and blood cells are to a large extent determined by the surrounding milieu: physicochemical factors, metabolism and hormones. It is thus difficult to delineate the specific role of adiposity, endothelial dysfunction, and the hormonal disturbance by its own in this complex picture. Nevertheless, low insulin sensitivity which is associated with both increased body fat and increased circulating lipids, together with impaired fibrinolysis, is characterized by a mild hyperviscosity syndrome. Those rheological alterations are more closely related to insulin resistance than to the clinical scoring of the metabolic syndrome. Low insulin sensitivity is associated with increased erythrocyte aggregability. When low insulin sensitivity is associated with hyperinsulinemia there is an increase in plasma viscosity. Among those factors, plasma viscosity appears, in multivariate analysis, to be "independently" related to insulin resistance. Moreover, plasma hyperviscosity is corrected by insulin-sensitizing procedures (such as exercise training) and is thus to some extent a marker of this disease.

Patients who have suffered a myocardial infarction (MI) and live with chronic heart failure (CHF) exhibit a substantial reduction in peripheral insulin sensitivity and increase their risk for developing diabetes by several-fold. To establish the putative role for post-myocardial infarction (MI) microcirculatory dysfunction in insulin resistance several questions must be addressed. Paramount amongst these are: 1. What are the microcirculatory hemodynamic characteristics in healthy resting muscle? 2. How are these impacted in post-infarction CHF? 3. Can current models of bloodtissue substrate delivery/exchange support a role for CHF-induced functional alterations in insulin resistance? This brief review considers that skeletal muscle, in part because of its great mass, prodigious capillarity and metabolic plasticity, constitutes a primary organ in body glucose homeostasis. The myriad changes in arteriolar vasoregulation post-MI, whilst certainly important with respect to the control of bulk muscle blood flow and its distribution, will not be addressed in depth herein. Rather, the questions posed above will be focussed within the context of recent novel observations at the capillary level i.e., at the primary site of blood-muscle exchange. These observations challenge the dogma that, in resting muscle, most capillaries are not recruited at rest which, if correct, would restrict their participation in glucose uptake and homeostasis. This is a crucial issue because direct observations suggest that, in healthy muscle, most capillaries do support continuous red blood cell (RBC) flux. In contrast, in post-MI CHF, a substantial proportion of skeletal muscle capillaries cease to support RBC flux both at rest and during contractions and it is likely that this constitutes a sentinel event in insulin resistance. Development and optimization of treatment strategies designed to ameliorate insulin resistance and halt or reverse the progression towards overt diabetes in CHF patients are dependent upon resolving these issues.

This chapter describes the arguments supporting our concept that microcirculatory defects may underlie insulin resistance (IR). Vascular (patho) physiology and metabolism are vast areas subjected to many confounding factors detailed here, which are cardinal to sort the many existing contradictory reports. A thorough analysis of the epidemiological and clinical literature clearly establishes that microvascular dysfunction and IR are linked and observable very early in life, well before metabolic syndrome and cardiometabolic diseases develop. In part 2 the thermodynamic, particularly microvascular effects of insulin itself are detailed and analyzed in terms of their physiological pertinence. Part 3 deals with underlying mechanisms, based on selected clinical situations. These reveal puzzling commonalities: together with cell physiology, they suggest that primary (inherited, early acquired) or secondary defects in sensing exaggerated physical forces of blood flow by the microvascular endothelial surface may be responsible. Glycocalyx and mainly caveolae, which are linked to vasomotor reactions and to insulin signalling and transport, are tentatively designed as the culprit.

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