Skip to main content
Download PDF
Download ePub

Neurohumoral stimulation in type-2-diabetes as an emerging disease concept

Cardiovascular Diabetology volume 3, Article number: 4 (2004) Cite this article

Abstract

Neurohumoral stimulation comprising both autonomic-nervous-system dysfunction and activation of hormonal systems including the renin-angiotensin-aldosterone system (RAAS) was found to be associated with Type-2-diabetes (T2D). Therapeutic strategies such as RAAS interference proved to be beneficial in both T2D treatment and prevention. In addition to an activated RAAS, hyperleptinemia in obesity, hyperinsulinemia in conditions of peripheral insulin resistance and overall oxidative stress in T2D represent known activators of the sympathetic component of the autonomic nervous system. Here, we hypothesize that sympathetic activation may cause peripheral insulin resistance defined as partial blocking of insulin effects on glucose uptake. Resulting hyperinsulinemia or hyperglycemia-related oxidative stress may further aggravate sympatho-excitation. This notion leads to a secondary hypothesis: sympathetic activation worsens from obesity towards insulin resistance, and further towards T2D. In this review, existing evidence relating to neurohumoral stimulation in T2D and consequences thereof, such as oxidative stress and inflammation, are discussed. The aim of this review is to provide a rationale for therapies, which are able to intercept neuroendocrine pathways in T2D and precursor states such as obesity.

Background

Both Type-2-Diabetes (T2D) and Chronic Heart Failure (CHF) may be perceived as consequences of originally diverse pathologies. In the CHF condition, the diagnosis of ischemic or non-ischemic etiology does not imply a different prognosis nor, with exception of antiarrhythmic strategies, treatment modality. Likewise, except for pancreatic-islet-transplant issues, the fundamental and adjunctive therapies for long standing, insulin-dependent T2D are the same, regardless the underlying reasons for T2D. Once advanced stages of T2D have been reached, different etiologies, i.e. genetically or environmentally caused T2D, appear of less importance to disease management and prognosis. Therefore, uniform disease mechanisms pertinent for disease progression in T2D need to be identified. As such a mechanism, neurohumoral stimulation comprising autonomic-nervous-system (ANS) dysfunction, i.e. sympathetic activation and vagal deactivation, as well as activation of hormones such as the renin-angiotensin-aldosterone system (RAAS) may be considered. The concept of neurohumoral stimulation was first applied to CHF, where plasma norepinephrine [1], atrial natriuretic peptide [2], B-type natriuretic peptide [3] and endothelin-1 [4] were found to be correlated with mortality or severity of disease. In T2D neurohumoral stimulation exists as well. There, ANS dysfunction [5] and the RAAS [6, 7] are critically involved. In addition, neurohumoral stimulation may involve adipose-tissue hormones given that obesity is one risk factor for T2D [8] as well as gastrointestinal neuropeptidergic inputs [9]. Hormone actions may affect insulin sensitivity, oxidative stress, inflammation and endothelial function (Table 1) as well as the ANS (Table 2).

Table 1 Hormone effects on insulin sensitivity, oxidative stress, inflammation and endothelial function.
Full size table
Table 2 Hormone effects on the autonomic nervous system.
Full size table

Presentation of the hypothesis

We hypothesize that persistent sympathetic-nervous-system activation actually represents one cause of peripheral insulin resistance (IR) defined as partial blocking of insulin effects on glucose uptake emphasizing oxidative stress and inflammation as possible links between neurohumoral stimulation and IR.

Testing the hypothesis

First, T2D-relevant hormones and the ANS are reviewed. Second, consequences of neurohumoral stimulation such as oxidative stress and inflammation are highlighted with regard to IR.

Insulin

Beyond the hypoglycemic action, insulin activates the sympathetic nervous system, while withdrawing the vagal component of the ANS [10, 11]. Furthermore, insulin enhances endothelial nitric-oxide synthase (eNOS) [12] which determines microvascular tone and may neutralize reactive oxygen species (ROS). We hypothesize that ANS dysfunction in terms of sympathetic activation, from whatever source, deteriorates peripheral insulin sensitivity, thus leading to repetitive hyperinsulinemia and hyperglycemia. If this hypothesis holds true, resulting hyperinsulinemia may further activate the sympathetic component of the ANS. Moreover, as hallmarks of type-2 diabetes, continued hyperinsulinemia may lead to pancreatic beta-cell exhaustion [15], while repetitive hyperglycemia may increase oxidative stress [13, 14].

Adipokines

Obesity is a major risk factor for T2D [16]. Adipokines such as leptin, resistin and adiponectin seem to be involved in IR. As stated in Figure 1, hyperleptinemia occurring in obesity directly activates the sympathetic nervous system [17–19]. Leptin increases oxidative stress [20], however, it may further attenuate interleukin activation [21]. Both leptin and resistin serum levels have been found to be associated with IR [22]. Conversely, the duodenum-derived ghrelin [9] and adiponectin [23, 24] were demonstrated to correlate with insulin sensitivity. ANS effects of resistin, adiponectin or of ghrelin are currently unknown. However, on endothelial cells, resistin promotes the release of endothelin-1 [25], known to be sympatho-excitatory [26]. Besides the possible role of adipokines on the ANS, cellular and subcellular adipocyte signalling issues may yield further insight into the special role of abdominal obesity for T2D [27].

Figure 1
figure 1

Relationships between known risk factors for T2D, neurohumoral factors and consequences thereof including oxidative stress and inflammatory response leading to peripheral IR and T2D. Blue arrows represent stimulation pathways, green arrow represents inhibition.

Full size image

Catecholamines

Catecholamines deteriorate insulin sensitivity as shown by high plasma concentrations of catecholamines in pheochromocytoma patients. There, insulin sensitivity was restored by tumor-removal surgery [28]. On the molecular level β-adrenergic stimulation itself inhibits insulin signaling molecules such as insulin receptor substrates, which have been shown to be essential for insulin action [29–31]. Furthermore, expression of adiponectin is inhibited, whereas IR-inducing IL-6 is stimulated by β-adrenergic activation in fat cells [32, 33]. However, beta-adrenergic receptor blocking drugs have not shown any effect on insulin sensitivity [34]. Both metabolic counteractive effects of beta-adrenergic blockade on pancreas-islet function and possibly still-active sympathetic stimulation via autonomic nerve fibers [35] may explain the lack of effect of beta-adrenergic blockade on IR. However, third-generation, vasodilating beta-blocking agents may set off possible adverse metabolic effects and confer a benefit for individuals having IR [36] bearing in mind that actions of epinephrine and norepinephrine include pro-oxidative [37] and proinflammatory effects [38, 39].

Renin-Angiotensin-Aldosterone System

Recent studies demonstrate the beneficial nature of therapeutic angiotensin-2 blockade in T2D using either angiotensin-converting-enzyme (ACE) inhibitors or direct angiotensin-2, subtype-1 receptor (AT1) antagonists [7, 40, 41]. Several mechanisms may account for this. First, angiotensin 2 acts as a sympathetic-nervous-system activator [42] and as a deactivator of vagal function [43]. Secondly, the activation of the RAAS facilitates the generation of free ROS via a NADPH-oxidase mechanism [44], leading to oxidative injury [45] and IR. Furthermore, angiotensin 2 elicits a pro-inflammatory, monocytic response [46]. Conversely, the blockade of the RAAS elicits a reduction of oxidative stress [47], a decrease of CRP as a marker of inflammation [48], a restoration of endothelial function [49], and an increase of adiponectin concentration [50], indicating an adipocyte-mediated amelioration of insulin sensitivity [23].

Aldosterone may independently contribute to adverse effects, given the observation, that aldosterone release may "escape" an ACE-inhibition or AT1 blockade [51]. Pharmacological or surgical correction of hyperaldosteronism has been shown to improve insulin sensitivity [52]. Moreover, an elevated plasma aldosterone is associated with pro-inflammatory and pro-oxidative effects [53] and may confer endothelial dysfunction [54]. Indirect evidence suggests aldosterone to be associated with an attenuated vagal [55] and cardiac sympathetic function [56]. However, especially for aldosterone effects on the sympathetic nervous system, there is no conclusive evidence available, yet.

Endothelin-1

Endothelin-1 is a most potent, mainly endothelially derived vasoconstrictor. Endothelin-1 concentrations were found to be increased in T2D [57]. Endothelin-receptor-A blockade improves endothelial dysfunction in T2D and obesity [58]. Moreover, chronic endothelin-1 application is associated with elevated oxidative stress [59, 60], inflammatory reaction within the arterial wall [61] and IR [62]. The principle of endothelin-1 blockade may, therefore, have beneficial effects in patients with T2D. Those effects may include an attenuation of prevalent sympatho-excitation as shown in the CHF condition [26].

Autonomic-nervous-system dysfunction as a cause of insulin resistance

Paradoxically, ANS dysfunction in terms of an activation of the sympathetic nervous system either increases or blunts insulin sensitivity. On the one hand, sympathetic activation may increase energy expenditure [63] and mediate lipolysis [64], thereby possibly reducing overweight as beta adrenergic blockade implies [65]. Thus, sympathetic activation may primarily serve as a compensatory mechanism. On the other hand, too much sympathetic activation may lead to IR: caffeine, eliciting sympathetic activation, has been shown to diminish peripheral-tissue insulin sensitivity [66]. Pheochromocytoma patients clearly have IR due to the high plasma concentrations of norepinephrine [28], and non-diabetic patients with sympatho-excitation due to spinal-chord injury were shown to have IR [67]. Moreover, heart-rate recovery following exercise-capacity tests as a measure of vagal function and predictor of cardiovascular mortality [68], correlates with insulin sensitivity [69]. Thus, once sympatho-activation or vagal deactivation is persistent, deleterious consequences such as IR may occur. Therefore, we hypothesize that sympatho-excitation, i.e. persistent sympathetic activation, may cause IR either directly via signalling effects within target cells or, indirectly, via oxidative-stress induced inflammatory responses. The attenuation of sympatho-excitation by centrally acting antiadrenergic drugs such as moxonidin slightly reduced IR [70] as a further indication of the validity of our hypothesis.

Mechanistically, a reduced nitric-oxide (NO) availability may be involved in the evolution of sympatho-excitation given the fact that certain eNOS polymorphisms are concomitant with a higher T2D and IR susceptibility [71]. Besides cardiovascular NO effects, central-nervous system NO may exert sympatho-inhibitory effects [72, 73].

Furthermore, life-style modifications such as exercise may restore ANS function in T2D or in precursor states via restoration of cardiovascular reflexes [74]. External factors, such as ethanol and tobacco consumption may further contribute to oxidative stress [75, 76] or sympathetic-nervous-system activation [77, 78].

The individual players of the overall concept of neurohumoral stimulation must still be characterized. As Figure 1 shows, the known T2D risk factors may ultimately affect the sympathetic nervous system, the RAAS and oxidative-stress milieu, once antioxidant pathways are saturated.

Oxidative stress and insulin resistance

Oxidative stress is a candidate mechanism connecting neurohumoral stimulation with IR [79], involving either an activated, vascular-smooth-muscle NADPH oxidase [44] or uncoupled nitric-oxide synthase. Those sources of "internal" oxidative-stress may be therapeutic targets. Other sources of internal oxidative stress, such as cytochrome-c leakage of superoxide anion, may be involved in (as well being the reason for) oxidative-stress sequelae such as carbonylation of proteins as seen in T2D [80]. Besides subcellular effects on insulin signalling [81], oxidative stress may lead to an activation of cytokines [82, 83] as well as to an activation of the sympathetic nervous system [84], possibly via desensitized afferent fibers of the sympatho-inhibitory baroreflex [85]. Thus, once RAAS-mediated oxidative stress is not compensated, another vicious cycle begins, aggravating IR towards T2D. According to Figure 2, it appears to be important to intervene in the possible vicious cycles involving the activation of the RAAS and the sympathetic nervous system. As both ACE inhibitors and AT1 antagonists interfere with the RAAS, hydroxy-methyl-glutaryl-CoA-reductase inhibitors or statins may have the potential to attenuate sympatho-excitation [73, 86] possibly by preventing NADPH oxidase activation as a source of endogenous oxidative stress [14, 87]. In both type-1 and type-2-diabetes mellitus, the latter drug clearly improved outcomes [88], however, peroral antioxidants did not [89]. One may argue that oxidative stress associated with T2D, atherosclerosis and hypertension is therapeutically accessible solely by drugs affecting internal sources of oxidative stress such as statins [88] or AT1 blockade [41]. Besides inflammation, vasodilatory or endothelial dysfunction may be another consequence of enhanced oxidative stress by ROS scavenging endothelial-cell derived nitric oxide [90].

Figure 2
figure 2

Suggested therapeutic interventions with regard to the framework of T2D risk factors and neurohumoral factors given in Figure 1. Solid lines across empty arrows signify blocked pathways; dotted lines across solid arrows represent attenuated pathways.

Full size image

Inflammation and insulin resistance

Inflammatory responses are likely to be due to oxidative-stress mediated alterations of cytokine expression including interleukin-6 [83]. Interleukin-6, in turn, elicits a CRP release from the liver [91]. The principle of ROS-mediated inflammation has been demonstrated using ultraviolet light [92, 93]. Although more research is needed, this suggested relationship may underly the inflammatory responses seen in atherosclerosis, obesity, and T2D. Prevalent inflammation may at least partially explain the occurrence of IR amid neurohumoral stimulation given the known roles of cytokines and of acute-phase reactants in IR [94, 95]. In fact, inflammation has been shown to be one risk factor for T2D [96]. As yet another proposed vicious cycle, repetitive hyperglycemia due to IR may further aggravate the oxidative stress [14] as well as the cytokine-mediated inflammatory response (Figure 1).

Implications of the hypothesis

The summarized evidence suggests that neuroendocrine mechanisms participate in T2D evolution. Neurohumoral stimulation is likely to be an important cause for the oxidative-stress milieu, the state of inflammation, and insulin resistance. Therefore, we propose the hypothesis that ANS dysfunction, most likely sympathetic-nervous-system activation, represents one cause of IR likely to be mediated by oxidative-stress induced inflammation. For both T2D treatment and prevention, this hypothesis may serve as a rationale for both pharmaceutical and non-pharmaceutical interventions to restore ANS tone and insulin sensitivity. Treatments, that are likely to affect ANS tone and insulin sensitivity may include RAAS interference, statin therapy, endothelin antagonism, or weight-control programs through exercise and/or hypocaloric diet (Figure 2). Because IR is difficult to measure, a practical approach may involve non-diabetic individuals having 'metabolic syndrome' [97]. Metabolic syndrome implies a 24.5-fold elevated risk for incidence of T2D [98] probably due to an underlying peripheral IR. Disturbed autonomic activity in terms of sympathetic activation and vagal deactivation may be a candidate mechanism for both the conversion processes of obesity to metabolic syndrome and of metabolic syndrome to T2D. Overall, clinical studies in T2D patients as well as in patients at risk for the development of T2D should determine ANS surrogates, such as muscle sympathetic nerve activity or heart rate variability, to further elucidate the role of ANS dysfunction in T2D evolution.

References

  1. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984, 311: 819-823.

    Article  CAS  PubMed  Google Scholar 

  2. Isnard R, Pousset F, Trochu J, Chafirovskaia O, Carayon A, Golmard J, Lechat P, Thomas D, Bouhour J, Komajda M: Prognostic value of neurohormonal activation and cardiopulmonary exercise testing in patients with chronic heart failure. Am J Cardiol. 2000, 86: 417-421. 10.1016/S0002-9149(00)00957-7.

    Article  CAS  PubMed  Google Scholar 

  3. Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R: B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation. 2002, 105: 2392-2397. 10.1161/01.CIR.0000016642.15031.34.

    Article  PubMed  Google Scholar 

  4. Rodeheffer RJ, Lerman A, Heublein DM, Burnett JC: Increased plasma concentrations of endothelin in congestive heart failure in humans. Mayo Clin Proc. 1992, 67: 719-724.

    Article  CAS  PubMed  Google Scholar 

  5. Carnethon MR, Golden SH, Folsom AR, Haskell W, Liao D: Prospective investigation of autonomic nervous system function and the development of type 2 diabetes: the Atherosclerosis Risk In Communities study, 1987–1998. Circulation. 2003, 107: 2190-2195. 10.1161/01.CIR.0000066324.74807.95.

    Article  PubMed  Google Scholar 

  6. Lindholm LH, Ibsen H, Borch J, Olsen MH, Wachtell K, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S: Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 2002, 20: 1879-1886. 10.1097/00004872-200209000-00035.

    Article  CAS  PubMed  Google Scholar 

  7. Brenner BM, Cooper ME, de Z, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001, 345: 861-869. 10.1056/NEJMoa011161.

    Article  CAS  PubMed  Google Scholar 

  8. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS: Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001. JAMA. 2003, 289: 76-79. 10.1001/jama.289.1.76.

    Article  PubMed  Google Scholar 

  9. Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O: Low Plasma Ghrelin Is Associated With Insulin Resistance, Hypertension, and the Prevalence of Type 2 Diabetes. Diabetes. 2003, 52: 2546-2553.

    Article  PubMed  Google Scholar 

  10. Muntzel MS, Anderson EA, Johnson AK, Mark AL: Mechanisms of insulin action on sympathetic nerve activity. Clin Exp Hypertens. 1995, 17: 39-50.

    Article  CAS  PubMed  Google Scholar 

  11. Van De Borne P, Hausberg M, Hoffman RP, Mark AL, Anderson EA: Hyperinsulinemia produces cardiac vagal withdrawal and nonuniform sympathetic activation in normal subjects. Am J Physiol. 1999, 276: R178-R183.

    CAS  PubMed  Google Scholar 

  12. Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL: Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo : a specific vascular action of insulin. Circulation. 2000, 101: 676-681.

    Article  CAS  PubMed  Google Scholar 

  13. Sampson MJ, Gopaul N, Davies IR, Hughes DA, Carrier MJ: Plasma F2 isoprostanes: direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes. Diabetes Care. 2002, 25: 537-541.

    Article  CAS  PubMed  Google Scholar 

  14. Christ M, Bauersachs J, Liebetrau C, Heck M, Gunther A, Wehling M: Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes. 2002, 51: 2648-2652.

    Article  CAS  PubMed  Google Scholar 

  15. Katsuragi I, Okeda T, Yoshimatsu H, Utsunomiya N, Ina K, Sakata T: Transplantation of normal islets into the portal vein of Otsuka Long Evans Tokushima Fatty rats prevents diabetic progression. Exp Biol Med. 2001, 226: 681-685.

    CAS  Google Scholar 

  16. Burke JP, Williams K, Narayan KM, Leibson C, Haffner SM, Stern MP: A population perspective on diabetes prevention: whom should we target for preventing weight gain?. Diabetes Care. 2003, 26: 1999-2004.

    Article  PubMed  Google Scholar 

  17. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI: Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997, 100: 270-278.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Gudbjornsdottir S, Lonnroth P, Sverrisdottir YB, Wallin BG, Elam M: Sympathetic Nerve Activity and Insulin in Obese Normotensive and Hypertensive Men. Hypertension. 1996, 27: 276-280.

    Article  CAS  PubMed  Google Scholar 

  19. Eikelis N, Schlaich M, Aggarwal A, Kaye D, Esler M: Interactions between leptin and the human sympathetic nervous system. Hypertension. 2003, 41: 1072-1079. 10.1161/01.HYP.0000066289.17754.49.

    Article  CAS  PubMed  Google Scholar 

  20. Beltowski J, Wojcicka G, Jamroz A: Leptin decreases plasma paraoxonase 1 (PON1) activity and induces oxidative stress: the possible novel mechanism for proatherogenic effect of chronic hyperleptinemia. Atherosclerosis. 2003, 170: 21-29. 10.1016/S0021-9150(03)00236-3.

    Article  CAS  PubMed  Google Scholar 

  21. Xiao E, Xia-Zhang L, Vulliemoz NR, Ferin M, Wardlaw SL: Leptin Modulates Inflammatory Cytokine and Neuroendocrine Responses to Endotoxin in the Primate. Endocrinology. 2003, 144: 4350-4353.

    Article  CAS  PubMed  Google Scholar 

  22. Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ: Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol. 2003, 149: 331-335.

    Article  CAS  PubMed  Google Scholar 

  23. Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C: Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes. 2002, 51: 1884-1888.

    Article  CAS  PubMed  Google Scholar 

  24. Pellme F, Smith U, Funahashi T, Matsuzawa Y, Brekke H, Wiklund O, Taskinen MR, Jansson PA: Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients. Diabetes. 2003, 52: 1182-1186.

    Article  CAS  PubMed  Google Scholar 

  25. Verma S, Li SH, Wang CH, Fedak PWM, Li RK, Weisel RD, Mickle DAG: Resistin Promotes Endothelial Cell Activation: Further Evidence of Adipokine-Endothelial Interaction. Circulation. 2003, 108: 736-740. 10.1161/01.CIR.0000084503.91330.49.

    Article  CAS  PubMed  Google Scholar 

  26. Liu JL, Pliquett RU, Brewer E, Cornish KG, Shen YT, Zucker IH: Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure. Am J Physiol Regul Integr Comp Physiol. 2001, 280: R1906-R1913.

    CAS  PubMed  Google Scholar 

  27. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ: Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. PNAS. 2003, 100: 10207-10212. 10.1073/pnas.1733877100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Wiesner TD, Bluher M, Windgassen M, Paschke R: Improvement of Insulin Sensitivity after Adrenalectomy in Patients with Pheochromocytoma. J Clin Endocrinol Metab. 2003, 88: 3632-3636. 10.1210/jc.2003-030000.

    Article  CAS  PubMed  Google Scholar 

  29. Fasshauer M, Klein J, Kriauciunas KM, Ueki K, Benito M, Kahn CR: Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Mol Cell Biol. 2001, 21: 319-329. 10.1128/MCB.21.1.319-329.2001.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Fasshauer M, Klein J, Ueki K, Kriauciunas KM, Benito M, White MF, Kahn CR: Essential role of insulin receptor substrate-2 in insulin stimulation of Glut4 translocation and glucose uptake in brown adipocytes. J Biol Chem. 2000, 275: 25494-25501. 10.1074/jbc.M004046200.

    Article  CAS  PubMed  Google Scholar 

  31. Klein J, Fasshauer M, Ito M, Lowell BB, Benito M, Kahn CR: beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes. J Biol Chem. 1999, 274: 34795-34802. 10.1074/jbc.274.49.34795.

    Article  CAS  PubMed  Google Scholar 

  32. Fasshauer M, Klein J, Lossner U, Paschke R: Interleukin (IL)-6 mRNA Expression is Stimulated by Insulin, Isoproterenol, Tumour Necrosis Factor Alpha, Growth Hormone, and IL-6 in 3T3-L1 Adipocytes. Horm Metab Res. 2003, 35: 147-152. 10.1055/s-2003-39075.

    Article  CAS  PubMed  Google Scholar 

  33. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R: Adiponectin gene expression is inhibited by beta-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett. 2001, 507: 142-146. 10.1016/S0014-5793(01)02960-X.

    Article  CAS  PubMed  Google Scholar 

  34. Kusunoki M, Oshida Y, Iguchi A, Iida T, Suga T, Funado T, Sato Y, Kato K, Sakamoto N: Influence of sympatho-adrenal system on insulin sensitivity using the euglycemic clamp technique. Diabetes Res Clin Pract. 1992, 17: 125-131. 10.1016/0168-8227(92)90157-M.

    Article  CAS  PubMed  Google Scholar 

  35. Turtzo LC, Marx R, Lane MD: Cross-talk between sympathetic neurons and adipocytes in coculture. PNAS. 2001, 98: 12385-12390. 10.1073/pnas.231478898.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Jacob S, Balletshofer B, Henriksen EJ, Volk A, Mehnert B, Loblein K, Haring HU, Rett K: Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers. Blood Press. 1999, 8: 261-268. 10.1080/080370599439463.

    Article  CAS  PubMed  Google Scholar 

  37. Aizawa T, Ishizaka N, Usui S, Ohashi N, Ohno M, Nagai R: Angiotensin II and catecholamines increase plasma levels of 8-epi-prostaglandin F(2alpha) with different pressor dependencies in rats. Hypertension. 2002, 39: 149-154. 10.1161/hy1201.097301.

    Article  CAS  PubMed  Google Scholar 

  38. Schade R, Gohler K, Burger W, Hirschelmann R: Modulation of rat C-reactive protein serum level by dexamethasone and adrenaline – comparison with the response of alpha 2-acute phase globulin. Agents Actions. 1987, 22: 280-287.

    Article  CAS  PubMed  Google Scholar 

  39. Takahashi T, Anzai T, Yoshikawa T, Maekawa Y, Asakura Y, Satoh T, Mitamura H, Ogawa S: Serum C-reactive protein elevation in left ventricular remodeling after acute myocardial infarction – role of neurohormones and cytokines. In J Cardiol. 2003, 88: 257-265. 10.1016/S0167-5273(02)00416-3.

    Google Scholar 

  40. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002, 359: 1004-1010. 10.1016/S0140-6736(02)08090-X.

    Article  CAS  PubMed  Google Scholar 

  41. Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000, 355: 253-259. 10.1016/S0140-6736(99)12323-7.

    Article  Google Scholar 

  42. Esler M: Differentiation in the effects of the angiotensin II receptor blocker class on autonomic function. J Hypertens. 2002, 20 (Suppl 5): S13-S19.

    CAS  Google Scholar 

  43. Le M, Mimassi N, Lancien F, Mabin D, Boucher JM, Blanc JJ: Heart rate variability, a target for the effects of angiotensin II in the brain of the trout Oncorhynchus mykiss. Brain Res. 2002, 947: 34-40. 10.1016/S0006-8993(02)02903-7.

    Article  Google Scholar 

  44. Sowers JR: Hypertension, Angiotensin II, and Oxidative Stress. N Engl J Med. 2002, 346: 1999-2001. 10.1056/NEJMe020054.

    Article  PubMed  Google Scholar 

  45. Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M: Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension. 2002, 40: 872-879. 10.1161/01.HYP.0000040262.48405.A8.

    Article  CAS  PubMed  Google Scholar 

  46. Kranzhofer R, Browatzki M, Schmidt J, Kubler W: Angiotensin II activates the proinflammatory transcription factor nuclear factor-kappaB in human monocytes. Biochem Biophys Res Commun. 1999, 257: 826-828. 10.1006/bbrc.1999.0543.

    Article  CAS  PubMed  Google Scholar 

  47. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, Shin MS, Ahn TH, Choi IS, Shin EK: Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol. 2003, 42: 905-910. 10.1016/S0735-1097(03)00846-5.

    Article  CAS  PubMed  Google Scholar 

  48. Takeda T, Hoshida S, Nishino M, Tanouchi J, Otsu K, Hori M: Relationship between effects of statins, aspirin and angiotensin II modulators on high-sensitive C-reactive protein levels. Atherosclerosis. 2003, 169: 155-158. 10.1016/S0021-9150(03)00158-8.

    Article  CAS  PubMed  Google Scholar 

  49. Hornig B, Kohler C, Schlink D, Tatge H, Drexler H: AT1-Receptor Antagonism Improves Endothelial Function in Coronary Artery Disease by a Bradykinin/B2-Receptor-Dependent Mechanism. Hypertension. 2003, 41: 1092-1095. 10.1161/01.HYP.0000064942.77814.26.

    Article  CAS  PubMed  Google Scholar 

  50. Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N, Yoshida D, Shimamoto K: Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension. 2003, 42: 76-81. 10.1161/01.HYP.0000078490.59735.6E.

    Article  CAS  PubMed  Google Scholar 

  51. Sato A, Hayashi K, Naruse M, Saruta T: Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003, 41: 64-68. 10.1161/01.HYP.0000044937.95080.E9.

    Article  CAS  PubMed  Google Scholar 

  52. Haluzik M, Sindelka G, Widimsky J, Prazny M, Zelinka T, Skrha J: Serum leptin levels in patients with primary hyperaldosteronism before and after treatment: relationships to insulin sensitivity. J Hum Hypertens. 2002, 16: 41-45. 10.1038/sj.jhh.1001292.

    Article  CAS  PubMed  Google Scholar 

  53. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT: Aldosterone-Induced Inflammation in the Rat Heart : Role of Oxidative Stress. Am J Pathol. 2002, 161: 1773-1781.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Kurbanov RD, Eliseeva MR, Tursunov RR, Kurbanova DR, Zakirova FA: [Humoral markers of endothelial dysfunction in essential hypertension]. Kardiologiia. 2003, 43: 61-64.

    CAS  PubMed  Google Scholar 

  55. Korkmaz ME, Muderrisoglu H, Ulucam M, Ozin B: Effects of spironolactone on heart rate variability and left ventricular systolic function in severe ischemic heart failure. Am J Cardiol. 2000, 86: 649-653. 10.1016/S0002-9149(00)01046-8.

    Article  CAS  PubMed  Google Scholar 

  56. Kasama S, Toyama T, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M: Effect of spironolactone on cardiac sympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2003, 41: 574-581. 10.1016/S0735-1097(02)02855-3.

    Article  CAS  PubMed  Google Scholar 

  57. Cardillo C, Campia U, Bryant MB, Panza JA: Increased Activity of Endogenous Endothelin in Patients With Type II Diabetes Mellitus. Circulation. 2002, 106: 1783-10.1161/01.CIR.0000032260.01569.64.

    Article  CAS  PubMed  Google Scholar 

  58. Mather KJ, Mirzamohammadi B, Lteif A, Steinberg HO, Baron AD: Endothelin Contributes to Basal Vascular Tone and Endothelial Dysfunction in Human Obesity and Type 2 Diabetes. Diabetes. 2002, 51: 3517-3523.

    Article  CAS  PubMed  Google Scholar 

  59. Duerrschmidt N, Wippich N, Goettsch W, Broemme HJ, Morawietz H: Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun. 2000, 269: 713-717. 10.1006/bbrc.2000.2354.

    Article  CAS  PubMed  Google Scholar 

  60. Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ, Chen AF: Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation. 2003, 107: 1053-1058. 10.1161/01.CIR.0000051459.74466.46.

    Article  CAS  PubMed  Google Scholar 

  61. Browatzki M, Schmidt J, Kubler W, Kranzhofer R: Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. Basic Res Cardiol. 2000, 95: 98-105. 10.1007/s003950050170.

    Article  CAS  PubMed  Google Scholar 

  62. Wilkes JJ, Hevener A, Olefsky J: Chronic endothelin-1 treatment leads to insulin resistance in vivo. Diabetes. 2003, 52: 1904-1909.

    Article  CAS  PubMed  Google Scholar 

  63. Hawkins MF, Avery DD: Effects of centrally-administered bombesin and adrenalectomy on behavioral thermoregulation and locomotor activity. Neuropharmacology. 1983, 22: 1249-1255. 10.1016/0028-3908(83)90197-1.

    Article  CAS  PubMed  Google Scholar 

  64. Hucking K, Hamilton W, Ellmerer M, Bergman RN: Burst-like control of lipolysis by the sympathetic nervous system in vivo. J Clin Invest. 2003, 111: 257-264. 10.1172/JCI200314466.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC: Hypothesis: Beta-adrenergic receptor blockers and weight gain: A systematic analysis. Hypertension. 2001, 37: 250-254.

    Article  CAS  PubMed  Google Scholar 

  66. Keijzers GB, De Galan BE, Tack CJ, Smits P: Caffeine Can Decrease Insulin Sensitivity in Humans. Diabetes Care. 2002, 25: 364.

    Article  CAS  PubMed  Google Scholar 

  67. Karlsson AK: Insulin resistance and sympathetic function in high spinal cord injury. Spinal Cord. 1999, 37: 494-500. 10.1038/sj.sc.3100844.

    Article  CAS  PubMed  Google Scholar 

  68. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS: Heart-Rate Recovery Immediately after Exercise as a Predictor of Mortality. N Engl J Med. 1999, 341: 1351-1357. 10.1056/NEJM199910283411804.

    Article  CAS  PubMed  Google Scholar 

  69. Lind L, Andren B: Heart rate recovery after exercise is related to the insulin resistance syndrome and heart rate variability in elderly men. Am Heart J. 2002, 144: 666-672. 10.1016/S0002-8703(02)00138-2.

    Article  PubMed  Google Scholar 

  70. Haenni A, Lithell H: Moxonidine improves insulin sensitivity in insulin-resistant hypertensives. J Hypertens. 1999, 17 (Suppl 3): S29-S35.

    CAS  Google Scholar 

  71. Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, Valsecchi G, Lucotti P, Pozza G, Bernardinelli L: Endothelial Nitric Oxide Synthase Polymorphisms Are Associated With Type 2 Diabetes and the Insulin Resistance Syndrome. Diabetes. 2003, 52: 1270.

    Article  CAS  PubMed  Google Scholar 

  72. Kishi T, Hirooka Y, Mukai Y, Shimokawa H, Takeshita A: Atorvastatin causes depressor and sympatho-inhibitory effects with upregulation of nitric oxide synthases in stroke-prone spontaneously hypertensive rats. J Hypertens. 2003, 21: 379-386. 10.1097/00004872-200302000-00030.

    Article  CAS  PubMed  Google Scholar 

  73. Pliquett RU, Cornish KG, Peuler JD, Zucker IH: Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation. 2003, 107: 2493-2498. 10.1161/01.CIR.0000065606.63163.B9.

    Article  CAS  PubMed  Google Scholar 

  74. De A, Schaan BD, Maeda CY, Dall A, Wichi RB, Irigoyen MC: Cardiovascular control in experimental diabetes. Braz J Med Biol Res. 2002, 35: 1091-1100.

    Article  Google Scholar 

  75. Kay HH, Grindle KM, Magness RR: Ethanol exposure induces oxidative stress and impairs nitric oxide availability in the human placental villi: a possible mechanism of toxicity. Am J Obstet Gynecol. 2000, 182: 682-688.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang J, Liu Y, Shi J, Larson DF, Watson RR: Side-stream cigarette smoke induces dose-response in systemic inflammatory cytokine production and oxidative stress. Exp Biol Med (Maywood). 2002, 227: 823-829.

    CAS  Google Scholar 

  77. Hausberg M, Mark AL, Winniford MD, Brown RE, Somers VK: Sympathetic and vascular effects of short-term passive smoke exposure in healthy nonsmokers. Circulation. 1997, 96: 282-287.

    CAS  PubMed  Google Scholar 

  78. Bennett AJ, Sponberg AC, Graham T, Suomi SJ, Higley JD, DePetrillo PB: Initial ethanol exposure results in decreased heart rate variability in ethanol-naive rhesus monkeys. Eur J Pharmacol. 2001, 433: 169-172. 10.1016/S0014-2999(01)01445-5.

    Article  CAS  PubMed  Google Scholar 

  79. Katsuki A, Sumida Y, Urakawa H, Gabazza EC, Murashima S, Nakatani K, Yano Y, Adachi Y: Increased Oxidative Stress Is Associated With Serum Levels of Triglyceride, Insulin Resistance, and Hyperinsulinemia in Japanese Metabolically Obese, Normal-Weight Men. Diabetes Care. 2004, 27: 631-632.

    Article  PubMed  Google Scholar 

  80. Dalle D, Giustarini D, Colombo R, Rossi R, Milzani A: Protein carbonylation in human diseases. Trends Mol Med. 2003, 9: 169-176. 10.1016/S1471-4914(03)00031-5.

    Article  Google Scholar 

  81. Tirosh A, Rudich A, Potashnik R, Bashan N: Oxidative stress impairs insulin but not platelet-derived growth factor signalling in 3T3-L1 adipocytes. Biochem J. 2001, 355: 757-763.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002, 106: 2067-2072. 10.1161/01.CIR.0000034509.14906.AE.

    Article  CAS  PubMed  Google Scholar 

  83. Frossi B, De C, Daniel KC, Rivera J, Pucillo C: Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway. Eur J Immunol. 2003, 33: 2168-2177. 10.1002/eji.200323995.

    Article  CAS  PubMed  Google Scholar 

  84. Girouard H, Chulak C, LeJossec M, Lamontagne D, De Champlain J: Chronic antioxidant treatment improves sympathetic functions and beta-adrenergic pathway in the spontaneously hypertensive rats. J Hypertens. 2003, 21: 179-188. 10.1097/00004872-200301000-00028.

    Article  CAS  PubMed  Google Scholar 

  85. Nightingale AK, Blackman DJ, Field R, Glover NJ, Pegge N, Mumford C, Schmitt M, Ellis GR, Morris T, Frenneaux MP: Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure. Clin Sci (Lond). 2003, 104: 529-535. 10.1042/CS20020334.

    Article  CAS  Google Scholar 

  86. Pliquett RU, Cornish KG, Zucker IH: Statin therapy restores sympathovagal balance in experimental heart failure. J Appl Physiol. 2003, 95: 700-704.

    Article  CAS  PubMed  Google Scholar 

  87. Maack C, Kartes T, Kilter H, Schafers HJ, Nickenig G, Bohm M, Laufs U: Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment. Circulation. 2003, 108: 1567-1574. 10.1161/01.CIR.0000091084.46500.BB.

    Article  CAS  PubMed  Google Scholar 

  88. Collins R, Armitage J, Parish S, Sleigh P, Peto R: MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003, 361: 2005-2016. 10.1016/S0140-6736(03)12475-0.

    Article  PubMed  Google Scholar 

  89. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002, 360: 23-33. 10.1016/S0140-6736(02)11807-1.

    Article  Google Scholar 

  90. Vaziri ND, Ni Z, Oveisi F, Liang K, Pandian R: Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension. 2002, 39: 135-141. 10.1161/hy0102.100540.

    Article  CAS  PubMed  Google Scholar 

  91. Yasunari K, Maeda K, Nakamura M, Yoshikawa J: Oxidative stress in leukocytes is a possible link between blood pressure, blood glucose, and C-reacting protein. Hypertension. 2002, 39: 777-780. 10.1161/hy0302.104670.

    Article  CAS  PubMed  Google Scholar 

  92. Urbanski A, Schwarz T, Neuner P, Krutmann J, Kirnbauer R, Kock A, Luger TA: Ultraviolet light induces increased circulating interleukin-6 in humans. J Invest Dermatol. 1990, 94: 808-811.

    Article  CAS  PubMed  Google Scholar 

  93. Hruza LL, Pentland AP: Mechanisms of UV-induced inflammation. J Invest Dermatol. 1993, 100: 35S-41S.

    Article  CAS  PubMed  Google Scholar 

  94. Festa A, Hanley AJ, Tracy RP, Agostino R, Haffner SM: Inflammation in the prediabetic state is related to increased insulin resistance rather than decreased insulin secretion. Circulation. 2003, 108: 1822-1830. 10.1161/01.CIR.0000091339.70120.53.

    Article  CAS  PubMed  Google Scholar 

  95. Festa A, Agostino R, Tracy RP, Haffner SM: Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002, 51: 1131-1137.

    Article  CAS  PubMed  Google Scholar 

  96. Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno N: Elevated C-Reactive Protein Is a Risk Factor for the Development of Type 2 Diabetes in Japanese Americans. Diabetes Care. 2003, 26: 2754-2757.

    Article  CAS  PubMed  Google Scholar 

  97. Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA: Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol. 2002, 156: 1070-1077. 10.1093/aje/kwf145.

    Article  PubMed  Google Scholar 

  98. Sattar N, Gaw A, Scherbakova O, Ford I, O'Reilly DS, Haffner SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM: Metabolic Syndrome With and Without C-Reactive Protein as a Predictor of Coronary Heart Disease and Diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003, 108: 414-419. 10.1161/01.CIR.0000080897.52664.94.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. M. Mann, University of Nebraska Medical Center, for his comments and help in the editing process.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Diabetology and Nephrology; Faculty of Medicine;, Leipzig University, D-04103, Leipzig, Germany

    RU Pliquett, M Fasshauer, M Blüher & R Paschke

Authors
  1. RU Pliquett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Fasshauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Blüher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Paschke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to RU Pliquett.

Additional information

Competing interests

None declared.

Authors' contributions

RUP constructed the hypothesis and drafted the manuscript. MF and MB added insight into the sections concerning adipokines and catecholamines. RP participated in finalizing the manuscript. All authors read and approved the manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pliquett, R., Fasshauer, M., Blüher, M. et al. Neurohumoral stimulation in type-2-diabetes as an emerging disease concept. Cardiovasc Diabetol 3, 4 (2004). https://doi.org/10.1186/1475-2840-3-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1475-2840-3-4

Keywords

  • diabetes mellitus
  • sympathetic nervous system
  • hormones
  • oxidative stress
  • inflammation

Cardiovascular Diabetology

ISSN: 1475-2840