Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions

Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1-40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.     

Effect of troglitazone on vascular and glucose metabolic actions of insulin in high-sucrose-fed rats

In rats, diets high in simple sugar induce insulin resistance and alter vascular reactivity. The present study was designed to evaluate the effects of 5 weeks treatment with troglitazone on insulin sensitivity, regional hemodynamics, and vascular responses to insulin in chow-fed and high-sucrose-fed rats. Male rats were randomly divided in 4 groups to receive a regular chow diet in the absence (group 1) or presence of troglitazone (0.2% in food; group 2), or a sucrose-enriched diet in the absence (group 3) or presence of troglitazone (group 4) for 5 weeks. The rats were instrumented with Doppler flow probes and intravascular catheters to determine blood pressure, heart rate, and regional blood flows. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique. Glucose transport activity was examined in isolated muscles. Sucrose feeding was found to induce insulin resistance and to impair the insulin-mediated skeletal muscle vasodilation. Treatment with troglitazone was found to increase whole-body insulin sensitivity in sucrose- and chow-fed rats, but had no effect on skeletal muscle glucose transport activity measured in isolated muscles from both dietary groups. Changes in regional hemodynamics were observed in both dietary cohorts treated with troglitazone, and the hindquarter vasoconstrictor response to insulin noted in sucrose-fed rats was abolished by the treatment. The vascular effects of troglitazone, and its insulin-related attenuating effects on contractile tone, could have contributed, in part, to improve insulin action on peripheral glucose disposal, presumably by improving blood flow distribution and glucose delivery.     

The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action

Evidence suggests that insulin delivery to skeletal muscle interstitium is the rate-limiting step in insulin-stimulated muscle glucose uptake and that this process is impaired by insulin resistance. In this review we examine the basis for the hypothesis that insulin acts on the vasculature at three discrete steps to enhance its own delivery to muscle: (1) relaxation of resistance vessels to increase total blood flow; (2) relaxation of pre-capillary arterioles to increase the microvascular exchange surface perfused within skeletal muscle (microvascular recruitment); and (3) the trans-endothelial transport (TET) of insulin. Insulin can relax resistance vessels and increase blood flow to skeletal muscle. However, there is controversy as to whether this occurs at physiological concentrations of, and exposure times to, insulin. The microvasculature is recruited more quickly and at lower insulin concentrations than are needed to increase total blood flow, a finding consistent with a physiological role for insulin in muscle insulin delivery. Microvascular recruitment is impaired by obesity, diabetes and nitric oxide synthase inhibitors. Insulin TET is a third potential site for regulating insulin delivery. This is underscored by the consistent finding that steady-state insulin concentrations in plasma are approximately twice those in muscle interstitium. Recent in vivo and in vitro findings suggest that insulin traverses the vascular endothelium via a trans-cellular, receptor-mediated pathway, and emerging data indicate that insulin acts on the endothelium to facilitate its own TET. Thus, muscle insulin delivery, which is rate-limiting for its metabolic action, is itself regulated by insulin at multiple steps. These findings highlight the need to further understand the role of the vascular actions of insulin in metabolic regulation.     

The metabolic actions of glucagon revisited

The initial identification of glucagon as a counter-regulatory hormone to insulin revealed this hormone to be of largely singular physiological and pharmacological purpose. Glucagon agonism, however, has also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity. Studies that describe novel preclinical applications of glucagon, alone and in concert with glucagon-like peptide 1 agonism, have revealed potential benefits of glucagon agonism in the treatment of the metabolic syndrome. Collectively, these observations challenge us to thoroughly investigate the physiology and therapeutic potential of insulin's long-known opponent.     

Differentiation of the metabolic and vascular effects of insulin in insulin resistance in patients with chronic heart failure

Chronic heart failure (HF) is associated with insulin resistance. Putative mechanisms of insulin resistance are abnormal skeletal muscle blood flow and antagonism of insulin action due to sympathetic nervous system activation. We measured insulin sensitivity, the vasoactive properties of insulin, and the association between insulin resistance and markers of neurohormonal activation in 10 patients with chronic HF and in 9 healthy controls. Noninvasive hemodynamic measurements and an hyperinsulinemic, euglycemic clamp were used. Patients were insulin resistant compared with the controls (p <0.05 for area under insulin dose-response curve). Insulin infusion led to a selective increase in forearm blood flow accompanied by a decrease in mean arterial pressure and superior mesenteric blood flow. Heart rate decreased in patients but not in controls; however, when baseline measurements were controlled for, there was no difference in the overall hemodynamic response to insulin infusion between the study groups. In univariate analysis, age, serum creatinine, fasting insulin, and triglyceride levels correlated inversely with insulin sensitivity (p <0.05 for all). Cardiac output had a significant correlation with insulin sensitivity (p <0.05). On stepwise multiple linear regression analysis, only age and fasting plasma insulin emerged as significant predictors of insulin sensitivity (R(2) 0.613, p = 0.001). In particular, we found no evidence of a relation between insulin sensitivity and plasma noradrenaline. Patients with chronic HF exhibit significant metabolic insulin resistance. Insulin resistance is not secondary to failure of insulin-mediated vasodilatation or sympathetic nervous system activation and is likely due to abnormalities at the level of the skeletal myocyte.     

Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium

Insulin has important vascular actions that regulate blood flow, in addition to its classical actions to coordinate glucose homeostasis. Insulin-stimulated production of nitric oxide in vascular endothelium results in capillary recruitment and vasodilation that diverts and increases blood flow to skeletal muscle and consequently increases glucose disposal. Thus, vascular actions of insulin may be essential for coupling hemodynamic and metabolic homeostasis. A complete biochemical signaling pathway linking the insulin receptor to activation of endothelial nitric oxide synthase in vascular endothelium has recently been elucidated. Moreover, the time course and dose response for capillary recruitment in response to physiologic concentrations of insulin parallels that of insulinmediated glucose uptake in vivo. Taken together, these observations suggest a molecular mechanism that may help to explain how insulin resistance contributes to cardiovascular components of the metabolic syndrome and vascular complications of diabetes.     

Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions

OBJECTIVE: In patients with essential hypertension, defects in both the metabolic and vascular actions of insulin have been described. Impaired microvascular function, a well-established abnormality in essential hypertension, may explain part of these defects. In the present study we investigated whether microvascular function is impaired in essential hypertension and relates to insulin's metabolic and vasodilatatory actions. METHODS: We measured 24-h ambulatory blood pressure, capillary recruitment after arterial occlusion, and skin blood flow responses to iontophoresis of acetylcholine and sodium nitroprusside in 18 subjects with untreated essential hypertension and in 18 control subjects. Whole body insulin sensitivity and leg insulin-mediated vasodilatation were assessed with the hyperinsulinaemic clamp technique and plethysmography. RESULTS: Hypertensive, as compared to normotensive, subjects had a decreased insulin sensitivity (0.8+/-0.3 vs. 1.7+/-0. 6 mgkg(-1)min(-1) per pmoll(-1); P<0.001), capillary recruitment after arterial occlusion (21.5+/-5.8 vs. 45.9+/-10.4%; P<0.001), acetylcholine-mediated vasodilatation (331+/-84 vs. 688+/-192%; P<0. 001), and insulin-mediated vasodilatation (median 29.3 vs. 47.2%; P<0.05). Correlation analyses with adjustment for sex, age, body mass index and waist-to-hip ratio showed significant relationships of capillary recruitment after arterial occlusion with blood pressure (r=-0.68; P<0.01), insulin sensitivity (r=+0.55; P<0.01) and insulin-mediated vasodilatation (r=+0.51; P<0.05), which extended from the normotensive to the hypertensive range. CONCLUSION: Skin microvascular function is associated with blood pressure and insulin's metabolic and vasodilatatory actions, both in normotensive and hypertensive subjects. These findings offer a potential mechanistic explanation of the links among insulin resistance, impaired insulin-mediated vasodilatation and hypertension.     

Dissection of the metabolic actions of insulin in adipocytes from early growth-retarded male rats.

Numerous studies have shown a relationship between early growth restriction and Type 2 diabetes. Studies have shown that offspring of rats fed a low protein (LP) diet during pregnancy and lactation have a worse glucose tolerance in late adult life compared with controls. In contrast, in young adult life LP offspring have a better glucose tolerance which is associated with increased insulin-stimulated glucose uptake into skeletal muscle. The aim of the present study was to compare the regulation of glucose uptake and lipolysis in adipocytes by insulin in control and LP offspring. LP adipocytes had increased basal and insulin-stimulated glucose uptake compared with controls. There was no difference in basal rates of lipolysis. Isoproterenol stimulated lipolysis in both groups, but it was more effective on LP adipocytes. Insulin reduced lipolytic rates in controls to basal levels but had a reduced effect in LP adipocytes. Protein kinase B activity matched glucose uptake, with LP adipocytes having elevated activities. These results suggest that early growth retardation has long-term effects on adipocyte metabolism. In addition, they show selective resistance to different metabolic actions of insulin and provide insight into the mechanisms by which insulin regulates glucose uptake and lipolysis.     

Cardiovascular actions of insulin

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.     

Vascular actions of insulin in obesity

An increased prevalence and incidence of cardiovascular disease is the most important clinical consequence of abdominal obesity. Although defects in glucose handling in skeletal muscle have been extensively investigated, they have failed to clarify why insulin resistance is linked to vascular disease. Non-classic actions of insulin such as those on haemodynamics, nerve function and haemostasis and on lipoprotein metabolism would appear of greater interest in this respect. It is now clear that obese individuals exhibit resistance to some of the non-classic effects of insulin. These include resistance to insulin action on large vessel compliance, nitric oxide-dependent stimulation of vasodilation in resistance vessels, activation of the sympathetic nervous system by insulin but not other stimuli, platelet anti-aggregation and suppression of hepatic very low density lipoprotein production. The exact cause(s) of resistance to these non-classic insulin actions are unclear but their understanding would seem important to understand the links between obesity and cardiovascular disease.     

胰岛素对血管的影响

胰岛素对机体生理功能的调节极为重要,当胰岛功能失调时可表现为胰岛素分泌减少及胰岛素抵抗。据统计,全世界每10秒钟就有1人死于胰岛功能失调相关并发症,在全球主要死亡疾病中排名逐年上升。不幸的是,约超过50％的患者没有意识到胰岛素对机体的重要性,导致死亡率也逐年增加。胰岛功能失调对动脉血管影响明显,可以导致相关的严重并发症,如心肌梗死、脑梗塞、肾功能衰竭等。因此,阐明胰岛素对动脉的影响,积极治疗是极其重要的。     

Thiazolidinediones: metabolic actions in vitro

To unravel the molecular mechanisms and the causal chain of how thiazolidinediones (TZDs) affect glucose homeostasis, it is helpful to analyse their direct influence on isolated specimens of fat, muscle, and liver in vitro. Studies on isolated adipocytes have shown that the nuclear peroxisome proliferator-activated receptor-gamma (PPAR gamma) is an important molecular target for TZDs, through which they trigger adipocyte differentiation and adipose tissue remodelling. It is not clear, however, if the activation of PPAR gamma in adipose tissue is the cause of all the metabolic actions of TZDs. Based on in vitro studies, two hypotheses have been developed. The first emphasizes PPAR gamma-mediated actions on adipose tissue, suggesting that insulin sensitization of skeletal muscle and liver is triggered indirectly by changes in circulating concentrations of adipocyte-derived non-esterified fatty acids and peptide hormones. The second states that TZDs improve glucose homeostasis independently from adipose tissue actions by the direct interaction with muscle and liver. This hypothesis is supported by direct TZD actions on fuel metabolism of skeletal muscle and liver in vitro, which seem to be independent from PPAR gamma signalling. Major progress has been made in understanding the mechanisms involved in the effects of TZDs on adipose tissue but the causal chain responsible for their antihyperglycaemic action is still not clear. The involvement of other molecular targets in addition to PPAR gamma, of adipocyte-derived messengers, and of direct interaction with skeletal muscle and liver have yet to be clarified.     

对胰岛素抵抗在代谢综合征中作用的新认识

代谢综合征(MS)是以中心性肥胖、高血压、脂质代谢异常、微量蛋白尿、葡萄糖耐量受损和(或)糖尿病等为特征的一组临床综合征,是导致糖尿病、心脑血管疾病的危险因素。1999年WHO将其正式命名为MS,并做了工作定义。2005年国际糖尿病联盟(IDF)对其提出了新的工作定义,进而达成全球共识。胰岛素抵抗是指机体对一定量胰岛素的生物学反应低于预计正常水平的一种现象,是导致MS发病的主要机制,其与MS各组分之间密切相关,但机制尚未完全阐明。本文就MS的定义及有关胰岛素抵抗在MS发生中的作用机制的研究的新进展做简要综述。     

Peripheral metabolic actions of leptin

The adipocyte-derived hormone, leptin, regulates food intake and systemic fuel metabolism; ob /ob mice, which lack functional leptin, exhibit an obesity syndrome that is similar to morbid obesity in humans. Leptin receptors are expressed most abundantly in the brain but are also present in several peripheral tissues. The role of leptin in controlling energy homeostasis has thus far focused on brain receptors and neuroendocrine pathways that regulate feeding behaviour and sympathetic nervous system activity. This chapter focuses on mounting evidence that leptin's effects on energy balance are also mediated by direct peripheral actions on key metabolic organs such as skeletal muscle, liver, pancreas and adipose tissue. Strong evidence indicates that peripheral leptin receptors regulate cellular lipid balance, favouring beta-oxidation over triacylglycerol storage. There are data to indicate that peripheral leptin also modulates glucose metabolism and insulin action; however, its precise role in controlling gluco-regulatory pathways remains uncertain and requires further investigation.     

Growth-stimulatory actions of insulin in vitro and in vivo

Insulin stimulates the growth and proliferation of a variety of somatic cells in culture, and evidence suggests that insulin is also an important regulator of growth in vivo. In cell culture, insulin interacts synergistically with other hormones and growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), tumor-promoting phorbol esters, and thrombin, to stimulate progression through the cell cycle of cells that have been arrested in G1 by deprivation for serum. In addition, insulin is required by most cells for optimal long term growth in hormone-supplemented serum-free media. In some cells, such as human skin fibroblasts, the growth-promoting effects of insulin appear to be mediated primarily by its low affinity interaction with receptors for insulin-like growth factor I (IGF-I). In other cells, such as hepatocytes, hepatoma cells, adrenocortical tumor cells, mammary carcinoma cells, and F9 embryonal carcinoma cells, insulin appears to stimulate growth by binding to high affinity insulin receptors. The insulin and IGF-I receptor proteins, like the receptor proteins for other growth-promoting hormones such as EGF and PDGF, are closely associated with tyrosine-specific protein kinase activities. The mechanism by which the binding of insulin to its receptor and activation of the receptor-associated tyrosine protein kinase activity control intracellular protein phosphorylation and dephosphorylation reactions, such as the phosphorylation of ribosomal protein S6, is a subject of considerable current interest. The phosphorylation of ribosomal protein S6 may be related mechanistically to the activation by insulin of protein synthesis, and hence the passage of cells through the G1 phase of the cell cycle. Malignant transformation does not generally result in a total loss of the growth requirement of cells for insulin or insulin-like growth factors, although transformation is accompanied in some cases by a qualitative reduction in the insulin/IGF requirement. Abnormalities in insulin production or sensitivity in vivo are accompanied by abnormalities in growth; thus, insulin appears to be an important regulator of growth in vivo. Some of the growth-promoting effects of insulin in vivo may be attributable to direct action of insulin, while other effects may be caused by the regulatory effect of insulin on somatomedin production, and possibly on somatomedin action.     

Circadian rhythms of insulin needs and actions

Circadian rhythms of insulin needs and action are a frequently discussed issue that is both of considerable physiological interest and of clinical importance in case of insulin substitution in type 1 diabetes. Basally, insulin is released in a pulsatile fashion which seemingly is erratic but at close analysis displays 'free-running' cyclical rhythmicity of 8-30 min duration that possibly guarantees optimal insulin action. This basal mode of insulin secretion is subject to a multitude of endogenous control systems that act on the B-cell both in a stimulatory (e.g., beta-agonists, glucagon as well as glucose and amino acids) and an inhibitory fashion (e.g., alpha-agonists, somatostatin). Since impairment of target cell sensitivity to insulin action and hyperglycemia may be caused by the stress hormones, cortisol, epinephrine and growth hormone included, with in part intrinsic rhythmicity, as well as by dehydration and by prolonged insulin withdrawal, a secondary feed-back signal on insulin release may easily be induced by rising blood glucose levels. In that modulators of insulin release and action are themselves secreted in a circadian fashion they tend to secondarily imprint the mode of insulin release. Therefore, any difference between a daily maximum and minimum in plasma insulin concentration besides its free-running short-term rhythmicity has to be regarded as a composite secondary circadian rhythm. It is in particular due to variable secondary early-morning and late-afternoon insulin resistance.     

Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.     

MicroRNAs in vascular and metabolic disease

Recent findings demonstrated the importance of microRNAs (miRNAs) in the vasculature and the orchestration of lipid metabolism and glucose homeostasis. MiRNA networks represent an additional layer of regulation for gene expression that absorbs perturbations and ensures the robustness of biological systems. This function is very elegantly demonstrated in cholesterol metabolism where miRNAs reducing cellular cholesterol export are embedded in the very same genes that increase cholesterol synthesis. Often their alteration does not affect normal development but changes under stress conditions and in disease. A detailed understanding of the molecular and cellular mechanisms of miRNA-mediated effects on metabolism and vascular pathophysiology could pave the way for the development of novel diagnostic markers and therapeutic approaches. In the first part of this review, we summarize the role of miRNAs in vascular and metabolic diseases and explore potential confounding effects by platelet miRNAs in preclinical models of cardiovascular disease. In the second part, we discuss experimental strategies for miRNA target identification and the challenges in attributing miRNA effects to specific cell types and single targets.