Natriuretic Peptides, Heart, andAdipose Tissue: New Findings andFuture Developments for DiabetesResearchDiabetes Care 2014;37:2899–2908 | DOI: 10.2337/dc14-0669

Natriuretic peptides (NPs) play a key role in cardiovascular homeostasis,counteracting the deleterious effects of volume and pressure overload andactivating antibrotic and antihypertrophic pathways in the heart. N-terminalB-type NP (NT-proBNP) also is a promising biomarker of global cardiovascularrisk in the general population, and there is increasing interest on its potentialuse in diabetic patients for screening of silent cardiovascular abnormalities,cardiovascular risk stratification, and guided intervention. Recently, both atrialNP (ANP) and B-type NP (BNP) have emerged as key mediators in the control ofmetabolic processes including the heart in the network of organs that regulateenergy usage and metabolism. Epidemiological studies have shown that ANPand BNP are reduced in people with obesity, insulin resistance, and diabetes,and this deficiency may contribute to enhance their global cardiovascular risk.Moreover, ANP and BNP have receptors in the adipose tissue, enhance lipoly-sis and energy expenditure, and modulate adipokine release and food intake.Therefore, low ANP and BNP levels may be not only a consequence but alsoa cause of obesity, and recent prospective studies have shown that low levelsof NT-proBNP and midregional proANP (MR-proANP) are a strong predictor oftype 2 diabetes onset. Whether ANP and BNP supplementation may result ineither cardiovascular or metabolic benefits in humans remains, however, to beestablished.

Natriuretic peptides (NPs) have gained great interest as indicators of the state ofcardiovascular health across the spectrum of cardiovascular diseases (CVD) in di-abetic subjects (1–4). Recently, NPs also have emerged as key mediators in thecontrol of metabolic processes (5) and have been implicated in the developmentof diabetes (6,7), shifting current paradigms and opening novel avenues in diabetesresearch. This review will summarize new findings in the field and discuss theirpotential clinical relevance.

NPS AND THEIR RECEPTORS

NPs are a family of genetically distinct and structurally related peptides, includingatrial NP (ANP), B-type NP (BNP), and C-type NP (CNP). They share a similar struc-tural conformation, characterized by a peptide ring with a cysteine bridge, which iswell preserved throughout evolution, being the portion of the chain that binds tothe receptor. ANP and BNP are predominantly secreted by cardiomyocytes, whereasCNP is mainly produced by the central nervous system, the endothelium, the bone,and the reproductive system (8–11).

Department of Medical Sciences, University ofTurin, Turin, Italy

Corresponding author: Graziella Bruno, graziella.bruno@unito.it.

Received 14 March 2014 and accepted 24 July2014.

© 2014 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

Gabriella Gruden, Andrea Landi, and

Graziella Bruno

Diabetes Care Volume 37, November 2014 2899

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Human NP genes encode for long in-active peptides that are processed toactive peptides and equimolar concen-trations of inactive fragments, whichhave a longer plasma half-life and arethus more suitable biomarkers for clini-cal use (12). ProANP is processed intoactive ANP and inactive fragments(N-terminal BNP [NT-proBNP] and mid-regional proANP [MR-proANP]) pre-dominantly by the enzyme corin (13).ProBNP, which is often posttranslation-ally O-glycosylated in the N-terminal re-gion, is cleaved into active BNP and theinactive fragment NT-proBNP by corinand furin (9). ProBNP can be releasedinto the bloodstream prior to processing(14), but has six- to eightfold lower ac-tivity than BNP. The CNP gene encodesfor a 126 prepropeptide that containsthe two active forms of CNP (CNP-22and CNP-53) and the inactive NT-proCNP fragment (11).The most important factor governing

ANP secretion is mechanical stretchingof the atria. ANP is stored in secretorygranules and stretching induces both se-cretion of previously synthesized ANPand increased ANP gene transcription.Stress of the ventricular wall due to vol-ume and/or pressure overload also isthe main inducer of BNP transcription(10,15). Circulating BNP and NT-proBNPlevels are quite low in the normal statebut rise in pathophysiological conditionscharacterized by fluid retention, suchas heart failure (HF) (16). In addition,hypoxia-response elements are pres-ent in the promoter region of the BNPgene and both myocardial ischemiaand hypoxia are potent BNP inducers(17). This explains why high BNP levelsare found in acute coronary syndromeor during exercise-induced ischemiadespite the absence of ventricular dilata-tion. Finally, ANP and BNP secretion canbe modulated by humoral factors, in-cluding endothelin-1, angiotensin II,sex steroids and thyroid hormones,glucocorticoids, and inflammatory cyto-kines (tumor necrosis factor-a [TNF-a],interleukin [IL]-1, IL-6) (8–10,18). CNPexpression is regulated by transforminggrowth factor-b1 (TGF-b1) and othergrowth factors in a cell- and tissue-specificmanner. In theendothelium,TGF-b, TNF-a,and IL-1 enhance CNP expression, whereasplatelet-derived growth factor–BB is themajor CNP inducer in vascular smoothmuscle cells (11).

ANP and BNP plasma levels are higherin women than in men and increase withage (19). There is preliminary evidencethat estrogens induce ANP and BNP pro-duction, whereas androgens suppress it;this may account for the sex differencesin plasma concentrations (20). PlasmaCNP levels are greater in men than inwomen, decline from adolescent to thefifth decade, and tend to increase there-after, particularly inmen (21). This is likelybecause both testosterone and growthhormone are potent CNP inducers (11).

NPs bind to high-affinity transmem-brane NP receptors (NPR)-A, NPR-B,NPR-C that share a relatively commonmolecular configuration. NPR-C bindsto all three peptides with similar affinity,whereas NPR-A and NPR-B differ in li-gand specificity (NPR-A: ANP.BNP..CNP; NPR-B: CNP..ANP$BNP); this,together with NPR tissue distribution,affects NP peripheral activity. Bindingto both NPR-A and NPR-B causes a con-formational change in the receptor mol-ecule that, in turn, activates particulateguanylyl-cyclase and increases intracel-lular cGMP that represents a second

messenger critical to NP activity. Bycontrast, binding to NPR-C results inNP internalization and enzymatic degra-dation, and NPR-C plays a key role inNP clearance (9,22) (Fig. 1). In additionto undergoing receptor-mediated deg-radation, NPs can be degraded by extra-cellular proteases, including neutralendopeptidase (NEP) and insulin-degrading enzyme (8,23). Moreover,cleavage of two N-terminal amino acidsfrom BNP by the enzyme dipeptidylpeptidase-4 (DPP-4) yields BNP3–32,which retains the physiologic effects ofBNP on the heart but has lower activityon both the kidney and the vessel wall(24). Other aminopeptidases can furtherdigest the N-terminal region of BNP andBNP3–32, leading to formation of break-down products (junk-BNP) of unclear bi-ological significance (25) (Fig. 2).

BIOLOGICAL ACTIONS OF NPS ANDMETABOLISM

Both ANP and BNP are important inmaintaining cardiovascular homeostasisand counteracting the deleterious ef-fects of volume and pressure overload.

Figure 1—ANP (red), BNP (blue), and CNP (green) NPs are secreted by the heart in response tovarious inducers and bind to high-affinity NPR-A, NPR-B, and NPR-C. NPR-C binds to all threepeptides with similar affinity, whereas NPR-A and NPR-B differ in ligand specificity (NPR-A:ANP.BNP..CNP; NPR-B: CNP..ANP$BNP). Binding to both NPR-A and NPR-B activatesparticulate guanylyl cyclase and increases intracellular cGMP leading to PKG activation. Bindingto the clearance NPR-C leads to NP internalization and enzymatic degradation. GTP, guanosine-5-triphosphate.

2900 Natriuretic Peptides and Diabetes Research Diabetes Care Volume 37, November 2014

Indeed, they act on the kidney to pro-mote diuresis and natriuresis, inducevasodilation, and protect the heartfrom high preload and afterload pres-sures, which can result in hypertrophyand fibrosis by activating antibrotic andantihypertrophic pathways (26–28). Inaddition, ANP and BNP reduce the sym-pathetic tone and suppress both reninand aldosterone secretion; therefore,they not only counterbalance but alsolower the activity of systems with op-posing renal and cardiovascular effects(29). Endothelial CNP, which is known toinduce vasorelaxation by hyperpolariza-tion of underlying vascular muscle cells,is a potential endothelium-derived hy-perpolarizing factor, participating inthe paracrine action of other endothe-lial vasorelaxant mediators, such as ni-tric oxide (NO) and prostacyclin (11).Our understanding of the physiology

of the NP system has dramatically in-creased in the past decades, and todaythe key role of NPs in cardiovascular

homeostasis is well established (see pre-vious reviews [26–29]); however, emerg-ing evidence suggests that the effects ofNPs extend beyond the cardiovascularsystem. As detailed below, NPR are ex-pressed in human adipose tissue, andNPs can stimulate lipolysis, promotebrowning of adipocytes, and also maymodulate adipokine secretion andfood intake (5,30–35). This previouslyunsuspected role of NPs in the regula-tion of metabolism is important as itraises the possibility that the heart be-longs to the network of endocrine or-gans that regulate energy usage andmetabolism. Furthermore, it may pro-vide new targets for therapeutic inter-vention in the fight against obesity andinsulin resistance.

The lipolytic effect of ANP was firstshown almost 20 years ago in physiolog-ical studies in humans. Intravenous in-fusion of ANP acutely increases plasmaconcentrations of both glycerol and freefatty acids (FFA) (36). Furthermore, ANP

infusion in human subcutaneous ab-dominal adipose tissue induces lipolysisand increases local blood flow, resultingin enhanced lipid mobilization (37). Ele-gant studies performed in humans sug-gest that FFA mobilized in response toANP may undergo mitochondrial oxida-tion in the liver, the skeletal muscle, andthe adipose tissue itself (37–39). In vitrostudies on adipocytes have partiallyclarified the underlying mechanism ofNP lipolytic activity. Activation of theNPR-A receptor induces a rise in cGMPlevels, followed by activation of proteinkinase G (PKG). PKG, in turn, phosphor-ylates perilipin, and this induces a phys-ical alteration of the lipid dropletsurface that facilitates activation ofboth adipose triglyceride lipase andhormone-sensitive lipase, thus trigger-ing lipolysis (35). The clearance recep-tor NPR-C reduces NPR-A–mediatedlipolysis by lowering local NP bioavail-ability. Indeed, rodents, which expressNPR-C at high levels on adipocytes,have a blunted lipolytic response toNPs, and NPR-C deletion rescues theirresponsiveness (32).

A recent breakthrough in our under-standing of role of NP on fat tissue me-tabolism has been the demonstrationthat in adipocytes NPR-A activation in-duces transcription of genes enhancingenergy expenditure and heat pro-duction (adipocyte browning) (32). Themost important gene encodes the mi-tochondrial transporter uncouplingprotein 1 (UCP1) that enables the sepa-ration of lipid oxidation from ATP pro-duction, allowing the conversion ofnutritional energy to heat. NPR-A activa-tion elicits this response by increasingp38a signaling and phosphorylationof ATF2, directly increasing PPARgcoactivator-1a [PGC-1a]) and UCP1 tran-scription. PGC-1a and UCP-1 promotemitochondrial biogenesis and both cou-pled and uncoupled respiration, and thisresults in enhanced energy expenditurethereby limiting white fat mass expan-sion. In line with these findings, NPR-Aknockout mice have an increased fatmass, whereas BNP infusion results in en-hanced energy expenditure in mice (32).

NPs also have a direct effect on theskeletal muscle, the major site of fueloxidation and energy expenditure.Transgenic mice overexpressing BNPand fed with a high-fat diet displayhigher expression of mitochondrial

Figure 2—Schematic representation of proBNP processing and cross-reactivity of assays mea-suring BNP and NT-proBNP. ProBNP can be posttranslationally O-glycosylated (O-glyc) within theGolgi apparatus. Both O-glycosylated and non-O-glycosylated proBNP are cleaved to BNP andNT-proBNP in equimolar fashion by the enzyme furin and then secreted into the circulation. Inthe bloodstream, BNP can be further degraded to BNP3–32 and other breakdown products(junk-BNP). ProBNP can be released prior to processing, particularly when O-glycosylated atposition Thr71 interferes with cleavage by furin, and may undergo processing into the blood-stream. Assays measuring BNP also recognized proBNP, BNP3–32, and junk-BNP (black square).Assays measuring NT-proBNP cross-react with proBNP (green square) but have poor reactivityfor O-glycosylated NT-proBNP and proBNP (dotted green square).

care.diabetesjournals.org Gruden, Landi, and Bruno 2901

oxidative genes in skeletal muscle (40).Furthermore, cultured human skeletalmuscle myotubes respond to both ANPand BNP with a significant increase inmitochondrial fat oxidative capacitythrough transcriptional activation ofPGC-1a and subsequent induction of ox-idative phosphorylation (OXPHOS) genesand mitochondrial respiration (39). ANPalso induces energy uncoupling, possiblyvia overexpression of UCP-3 and adeninenucleotide translocase 1, which accountsfor 50%of basal (noninduced) proton leak(41). Notably, an upregulation of NPR-A,PGC-1a, and OXPHOS genes is observedin the skeletalmuscle of obese subjects inresponse to an aerobic exercise trainingprogram, suggesting that some of themetabolic adaptations of skeletal musclein response to chronic exercise may bemediated by ANP and BNP (39).Data on the interplay between the NP

system and cytokines released by the fattissue are still limited. However, in vitroin human adipocytes, ANP inhibits leptinrelease and both ANP and BNP enhanceadiponectin secretion via NPR-A (33). Inaddition, in adipose tissue explants, ANPreduces IL-6, TNF-a, MCP-1, and leptinsecretion (35). Finally, ANP infusion en-hances adiponectin plasma levels in hu-mans (42). Collectively, these findingssuggest that NPR-A activation may mod-ulate adipokine secretion and has a ben-eficial effect on low-grade inflammationof the adipose tissue and thus insulinresistance.Recent studies suggest that NPs are

involved in food intake control. A studyperformed in healthy fasting volunteershas shown that BNP infusion decreaseshunger and increases satiety, possiblyby lowering circulating ghrelin levels(34). Ghrelin also has direct cardiovas-cular effects (43), and this supports theexistence of a bidirectional heart–gutcross talk. In addition, the high expres-sion of NPR-B, the main CNP receptor, inthe arcuate nucleus of the hypothala-mus suggests a role of CNP in the controlof food intake. Consistently, a recent ex-perimental study has shown that centraladministration of CNP reduces food in-take and body weight, partially throughactivation of the hypothalamic melano-cortin pathway, which also is engagedby leptin and serotonin (44). Recently,Kim et al. (45) have described an entire-ly new mechanism in the control ofANP release from the heart by the

gut-released hormone GLP-1, revealing anew gut–heart connection. Activation ofGLP-1 receptors in the atrial myocar-dium induces ANP secretion, resultingin vasodilation, natriuresis, and reducedblood pressure. Therefore, an increasein nutrients after a meal triggers a gut-mediated response, leading not only toeffective regulation of insulin and gluca-gon release through a direct GLP-1 effectbut also to indirect metabolic and hemo-dynamic changes mediated by ANP.ANP-induced vasodilation may be advan-tageous in this setting as it may promotean increased blood supply to the gut andadipose tissue, thus resulting in betterabsorption and distribution of nutrients(45,46).

The key role of insulin in metabolismhas prompted studies on the potentialinterplay between NPs and b-cells. Invitro ANP induces insulin secretion inan NPR-A–dependent manner by in-creasing Ca21 influx through blockadeof ATP-sensitive K1 channels. Further-more, ANP increases the insulin contentof isolated islets, and NPR-A knockoutmice have lower insulin levels in freshlyisolated islets, reduced b-cell mass, andhigher fasting blood glucose levels (47).In keeping with these data, ANP infusionenhances insulin secretion in humans inthe fasted state and in response to ameal test (37,48).

Only a few studies have assessed theeffect of NP infusion on glucose homeo-stasis. In fasting healthy men, an acutehigh-dose ANP infusion induces a mod-est increase in blood glucose that islikely due to enhanced FFA mobilizationleading to increased gluconeogenesis(38). Short-term BNP infusion in healthyvolunteers during an intravenous glu-cose tolerance test reduces the rise inblood glucose levels as compared withsaline. This occurs without changes ininsulin secretion and sensitivity andprobably results from enhanced glucosevolume distribution (49). These physio-logical studies do not, however, ad-dress the far more relevant issue ofthe long-term effects of chronic NPtreatment on glucose metabolism. Thishas not yet been investigated in humans;however, a recent study in db/db micehas shown that chronic BNP infusioninduces a significant reduction in bloodglucose levels (50).

Obviously there is much additionalwork to be done in both basic and

clinical research to fully understandthe function of the NP system in meta-bolic processes. However, emerging ev-idence indicating that NPs are themediators of a novel “heart-adiposeaxis” has opened the way to an entirelynovel and exciting area of research withpotentially high clinical impact.

NPS AND OBESITY, DIABETES, ANDDIABETES COMPLICATIONS

ObesityObesity is associated with decreased cir-culating levels of ANP and BNP, and anegative linear relationship betweenBMI and NP plasma values has been con-sistently reported in epidemiologicalstudies (5,35,51). Conversely, weightloss increases NT-proBNP levels (52).There also is evidence that a reductionin NP levels is associated to a less favor-able adipose tissue distribution profile.Recent data from the Dallas Heart Studyshow that both BNP and NT-proBNP areinversely associated with visceral andliver fat and positively associated withlower glutofemoral body fat, indepen-dent of confounders including insulinresistance (53).

Central obesity is a key feature of themetabolic syndrome (MetS); it is, how-ever, still matter of debate if BNP andNT-proBNP levels are reduced in MetS,with studies reporting either lower orunchanged values. This is likely due todifferences among examined popula-tions in the relative frequencies ofMetS components with opposite effectson BNP. Consistently, a recent longitu-dinal study performed on 3,019 Afri-can Americans has shown that bothlower and higher BNP levels were pre-dictors of incident MetS in a nonlinearU-shape relationship, likely a reflec-tion of lower BNP relation to obesityand higher BNP relation to blood pres-sure (54).

The cause of the relative ANP and BNPdeficiency seen in obesity (natriuretichandicap) is poorly understood, but itis of clinical relevance as it may exposeobese patients to enhanced cardiovas-cular risk and represent a potentialmechanism behind the frequent cluster-ing of obesity and hypertension. Almosttwo decades ago, researchers interestedin the relationship between obesity andhypertension noted that levels of theclearance NPR-C were markedly ele-vated in obese subjects. The underlying

2902 Natriuretic Peptides and Diabetes Research Diabetes Care Volume 37, November 2014

mechanism remains elusive; however,food intake and insulin resistance arelikely involved as adipose tissue NPR-Cexpression is increased by a high-fatdiet, correlates with fasting insulin, andis reduced by pharmacological strategiesimproving insulin sensitivity (5,40). Re-gardless of the mechanism, the observa-tion that NPR-C is overexpressed inobese subjects fueled speculation thatincreased NP clearance could explainthe “natriuretic handicap.” However,both NT-proBNP and NT-proANP, whichare not cleared by NPR-C, show a similarinverse relationship with BMI, makingthis hypothesis less likely. In addition, re-cent data indicate that NPs are mainlycleared by NEP.Alternatively, ANP and BNP levels

may be reduced in obesity becauseof a lower synthesis and/or releasefrom the heart. In keeping with this hy-pothesis, cardiac mRNA expression ofboth ANP and BNP is reduced in obeseZucker fatty rats and db/dbmice (50,55).Data in humans are limited; however,a study in subjects who underwent car-diac catheterization has shown thatcardiac BNP release is inversely andindependently related to BMI (56).Obese individuals may be prone to a rel-ative NP deficiency, stemming fromsuppressive effects of circulating an-drogens on ANP and BNP synthesis(57) and possibly from the deleterioussystemic and local effects of cardiacectopic fat on NP synthesis and re-lease (58,59). Consistently, downregula-tion of cardiac ANP and BNP expressionis paralleled by a rise in cardiac triglyc-erides content in animal models ofobesity, and oleic acid reduces ANPmRNA levels in cultured cardiomyo-cytes (60).On the other hand, the recently dis-

covered effects of NPs on metabolismand energy expenditure raise the possi-bility that NP deficiency may directlycontribute to the development and wors-ening of obesity and dysmetabolism. In-deed, in obese and insulin-resistantsubjects, reduced ANP and BNP levelsand upregulation of the clearance NPR-Cin the adipose tissue may hamper theability of the local NP system to enhancelipolysis and energy expenditure (5). Inkeeping with this hypothesis, targeteddeletion of the NPR-C gene in rodentsresults in a lean phenotype, transgenicBNP mice fed with a high-fat diet are

protected from obesity and insulin resis-tance, and chronic BNP infusion im-proves the metabolic profile of db/dbmice, including a reduction in fat content(32,40,50).

DiabetesGrowing evidence of a role of NPs inobesity and insulin resistance raisesthe question of whether NP deficiencyis implicated in the development oftype 2 diabetes (T2D). Recently, twolarge and well-designed prospectivestudies have substantiated this hypoth-esis. In the Malmo Diet and CancerStudy (6), MR-ANP and NT-proBNPlevels were measured in 1,828 nondia-betic individuals who subsequentlyunderwent a 16-year follow-up exam,including an oral glucose tolerancetest. Results showed that low MR-ANPplasma levels predict development offuture diabetes. After full adjustment,the odds ratio for incident diabetes inthe bottom compared with the topquartile of MR-ANP was 1.65 (95% CI1.08–2.51), independent of confound-ers. An inverse, but not statistically sig-nificant, association was found betweenNT-proBNP and diabetes risk. In the samecohort, the variant rs5068within the ANPgene, which results in enhanced plasmaANP levels, was associated with a 12%reduced adjusted-risk of incident diabe-tes (61). Furthermore, other studieshave reported that the rs5068 variant isassociated with lower BMI, waist circum-ference, and prevalence of obesity andMetS (62,63).

In the longitudinal AtherosclerosisRisk in Communities Study (ARIC) (7),which examined 7,822 nondiabetic indi-viduals, with respect toNT-proBNP valuesin the highest quartile (.114 pg/mL), val-ues in the lowest quartile (,31 pg/mL)were associated with higher risk of inci-dent diabetes over a 12-year follow-upperiod, independent of confounders andrisk factors (hazard ratio 0.75 [95% CI0.64–0.87]). A significant linear trendacross quartiles also was evident, evenafter stratification by BMI (7). Fur-thermore, a common genetic BNP vari-ant (rs198389), which results in a 20%increase in plasma BNP levels, was foundto be associated with a 15% reduced riskof T2D (64). See Table 1 for a summary ofhuman studies (6,7,61,64,65).

Insight on the mechanisms wherebyNP deficiencymay enhance diabetes risk

is still insufficient. In the Malmo andARIC studies, the prospective relation-ship between MR-ANP and NT-proBNPand diabetes remained significant afteradjustment for insulin resistance, indi-cating that alternative mechanisms,such as NPR-A–induced energy expen-diture, adiponectin secretion, and im-proved b-cell function, may be involved(Fig. 3). Regardless of the mechanism,the evidence that low NP levels areimplicated in the development of diabe-tes together with the well-establishedrole of low NPs in hypertension andCVD suggests that NP deficiency maybe a link between the relevant clinicalproblem of shared propensity to diabe-tes, hypertension, and CVD. Moreover,it suggests that NT-proBNP and MR-ANP may be used as biomarker fordiabetes prediction. Further studies are,however, required to establish clinicalrelevance.

Diabetes ComplicationsBoth BNP and NT-proBNP are well-established diagnostic and prognosticbiomarkers of HF in both diabetic andnondiabetic subjects (16). AlthoughBNP and NT-proBNP levels appear ele-vated in patients with HF, the fraction ofactive BNP is relatively small. Currentassays cross-react with poorly activeBNP-related peptides (proBNP, BNP3–32,junk-BNP) (Fig. 2), whose levels are in-creased in HF, and they thus overestimateplasma and serum BNP and NT-proBNPvalues (25). Altered cardiac processing ofproBNP to BNP is a likely explanation forthe rise in circulating proBNP levels in HF.Notably, a recent study in humans hasshown that cardiac proBNP release wasgreater in patients with HF and that theonly variable positively associated withenhanced proBNP secretion was diabe-tes (14). This suggests that HF, particu-larly in diabetes, affects either theexpression and activity of proBNP cleav-ing enzymes or proBNP glycosylation, amodification that changes proBNP sus-ceptibility to cleavage by furin, particu-larly when it occurs at Thr71 (25). Onthe other hand, studies in db/dbmice sug-gest that both enhanced BNP3–32 forma-tion and resistance to mechanisms ofproBNP clearance from the circulationalsomay contribute to increase circulatingBNP immunoreactivity in diabetes (50).

BNP and NT-proBNP are not alwaysreliable biomarkers for HF diagnosis as

care.diabetesjournals.org Gruden, Landi, and Bruno 2903

30% of symptomatic HF patients withpreserved ejection fraction (HFPEF)have normal BNP and NT-proBNP levels(66). This is of relevance to diabetes asHFPEF prevalence is very high in T2D andthe relative risk of cardiovascular deathor HF hospitalization conferred by dia-betes is significantly greater in HFPEFthan in HF with reduced ejection frac-tion (HFREF) (67,68). Recently, studiesperformed on myocardial tissue frompatients with HFPEF and left ventricular(LV) diastolic dysfunction have givennew insight on the potential relation-ship between diabetes, HFPEF, andBNP. According to a novel proposed par-adigm for the pathogenesis of HFPEF, asystemic inflammatory state inducedby obesity, diabetes, and other comor-bidities causes oxidative stress in thecoronary microvascular endothelium,reducing myocardial NO bioavailabilityand leading to reduced PKG activity incardiomyocytes, which therefore be-come stiff and hypertrophied (69). AsBNP gene expression is regulated by di-astolic LV wall stress, which is lower inHFPEF because of prevailing concentricLV remodeling, this is not compensatedby an enhanced BNP production. Consis-tently, myocardial BNP expression islower in patients with HFPEF than inthose with HFREF (70). This raises thepossibility that drugs increasing BNP lev-els may represent a novel therapeuticstrategy in patients with HFPEF andthe PARAGON-HF trial is under develop-ment to test this hypothesis.

Besides HF, BNP and NT-proBNP canprovide quantitative information aboutthe state of cardiovascular health acrossthe full spectrum of CVD, and there isincreasing interest on their potentialrole as predictors and biomarkers ofcomplications and cardiovascular mor-tality in diabetes. A prospective studyperformed on 315 T2D patients showedthat NT-proBNP levels were greater inpatients with albuminuria. Further-more, NT-proBNPwas a strong predictorof all-cause and cardiovascular mortalityindependent of potential confoundingrisk factors and had a predictive valuefor all-cause mortality comparable tothat of microalbuminuria (1). Consis-tently, we have recently reported thatNT-proBNP was strongly and indepen-dently associated with cardiovascularmortality in a longitudinal study per-formed on a large cohort of 1,825 T2D

Table

1—NPsandtherisk

ofT2D

inhuman

epidemiological

studies

Study

Studydesign

Studypopulation

NBiomarkers/gen

evariant

Even

tAdjusted

OR/H

R(95%

CI)

MalmoStudy

(6)

Prospective

study(16-year

follow-up)

Swed

ish,n

ohistory

of

diabetes,*

CVD,HF

1,82

8MR-ANP,

NT-proBNP

Inciden

tdiabetes

(301

even

ts:

OGTT)

MR-ANP,

OR0.85(0.73–

0.99)

per

SD;NT-proBNP,O

R0.92

(80–

1.06)

per

SD

ARIC

Study

(7)

Prospective

study(12-year

follow-up)

U.S.,nohistory

of

diabetes,*

CVD,

HF,CKD

7,82

2NT-proBNP

Inciden

tdiabetes

(1,740

even

ts:

self-rep

orted

,med

ications)

4thNT-proBNPquartilevs.1st

quartile,H

R0.75(0.64–

0.87)

FINRISK97

Study(65)

Prospective

study(10.8-year

follow-up)

Finnish,n

ohistory

of

diabetes,*

5%knownCVD

7,82

7NT-proBNP

Inciden

tdiabetes

(417

even

ts:

nationalregisters)

NT-proBNP,

HR0.82(0.73–

0.93)

per

SD

Pfister

etal.

(64)

Case-cohortstudynestedin

the

EPIC-Norfolkstudy

Norfolk,U

.K.,nohistory

of

diabetes,C

VD

440cases,74

0control

subjects

NT-proBNP

T2D(440

cases:self-rep

orted

,med

ications,nationalregisters)

HR0.79

(0.64–

0.97)

per

SD

Pfister

etal.

(64)

Men

delianrandomization

study:meta-an

alysis

of11

case-controlstudies

Europeandescent

23,382

cases,57

,898

controlsubjects

Callelers198

389

inBNPlocus

T2D(23,38

2cases)

OR0.94(0.91–

0.97)

per

allele

MalmoStudy

(61)

Men

delianrandomizationstudy

(14-year

follow-up)

Swed

ish,n

ohistory

of

diabetes**

27,307

OnecopyoftheG

allelers50

68in

theANPlocus

Inciden

tdiabetes

(2,823

even

ts:

nationalregistries)

HR0.88

(0.78–

0.99)

per

allele

CKD

,chronickidney

disease;HR,hazardratio;OGTT,o

ralglucose

tolerance

test;OR,oddsratio.*Fastingglucose

availableat

baseline.

**Fastingglucose

availablein

asubgroup.

2904 Natriuretic Peptides and Diabetes Research Diabetes Care Volume 37, November 2014

patients from the population-based Ca-sale Monferrato Study (71), and in thesame cohort, NT-proBNP also was anegative confounder in the associ-ation between central obesity and car-diovascular death (72). Similarly, in type1 diabetes NT-proBNP is associated withmicro- andmacrovascular complicationsand is a predictor of cardiovascular mor-tality (73,74). Recent studies also havedemonstrated that NT-proBNP predictscardiovascular events in T2D patientsand has a greater predictive value thanother well-established cardiac riskmarkers (2,75,76). Collectively, thesedata suggest the possible use of NT-proBNP as a tool for risk stratification,and preliminary data support thisapproach. In the Action in Diabetesand Vascular Disease: Preterax andDiamicron MR Controlled Evaluation(ADVANCE) study, NT-proBNP greatlyimproved the accuracy with which therisk of cardiovascular events or deathcould be estimated in T2D patients andprovided much more prognostic infor-mation than cholesterol or C-reactiveprotein (77). An additive effect ofNT-proBNP and albuminuria in pre-dicting cardiovascular mortality was,however, observed in the CasaleMonferrato Study, suggesting that theparallel assessment of both may

provide additional information for riskassessment (71).

NT-proBNP and BNP levels also mirrorclinically silent processes in the cardio-vascular system that gradually shift thehomeostatic balance from health to dis-ease far before cardiac events occur,and they are bothmarkers and predictorsof earlier cardiac abnormalities in di-abetic patients. In the Hoorn Study(3), a slight increase in baseline BNPlevels was a strong predictor of bothLV hypertrophy and diastolic LV dys-function, and this association was par-ticularly evident in T2D patients. Inasymptomatic T2D patients, NT-proBNPwas associated with silent myocardialischemia independent of microalbumin-uria. Furthermore, a 10-year longitudinalstudy performed on asymptomatichigh-risk diabetic patients found thatNT-proBNP$38 pg/mL was the only in-dependent predictor of silent coronaryartery disease (4). Hypoxia and myocar-dial wall strain are likely inducers of BNPin these settings. In addition, inflamma-tory cytokines also may be involved asboth TNF-a and IL-6 induce BNP secre-tion in cultured cardiomyocytes, theirplasma levels rise prior to that ofNT-proBNP in hypertensive subjects(78), and the association between NT-proBNP and vascular complications was

dependent on TNF-a in the EURODIABstudy (73). A strategy that selects asymp-tomatic T2D patients, based on BNP andNT-proBNP levels, for further investiga-tion (e.g., echocardiography, stress test-ing) is very attractive. Supporting dataare still scarce; however, Nadir et al.(79) have recently reported that in acommunity cohort BNP measurementwas an optimal screening test to identifyindividuals with silent cardiac damagefor further assessment. In addition, NT-proBNP may be proposed as a tool toguide intervention for primary preven-tion. In the Casale Monferrato study(71), NT-proBNP was prospectively asso-ciated with cardiovascular mortalityeven in normoalbuminuric patientswithout CVD at baseline, indicatingthat NT-proBNP may be useful for iden-tification and treatment of patientswith a hitherto unknown high risk ofcardiovascular death. A prospectiverandomized controlled trial has re-cently substantiated this hypothesisby showing a remarkable 65% reduc-tion in the risk of the primary endpoint of hospitalization or cardiacdeath in T2D patients with NT-proBNPlevels greater than .125 pg/mL and noknown cardiac disease randomized to abiomarker-guided “intensified” treat-ment (80).

Taken together, epidemiological ev-idence summarized here indicates thatBNP and NT-proBNP are importantbiomarkers of CVD complications inpatients with diabetes. The “clinicalparadox” of BNP and NT-proBNP beingnegative predictors of diabetes and posi-tive predictors of diabetes complicationsis unexplained; however, a possible inter-pretation is that changes in BNP andNT-proBNP levels reflect different patho-physiological processes in subjects at riskfor diabetes and in those at risk for dia-betes complications. In obese subjects,reduced BNP and NT-proBNP levels maymirror a deficiency in BNP synthesis, con-tributing to dysmetabolism and diabetesonset. On the contrary, in diabetic pa-tients an increase in BNP and NT-proBNPlevels may reflect proBNP accumulationthat masks the linear relationship be-tween residual active BNP and metabolicparameters, but being the result ofaltered cardiac processing is a valuablebiomarker of early cardiac and hemody-namic abnormalities and of the inabilityof the heart to effectively counteract

Figure 3—Potential link between NPs, obesity, insulin resistance, and diabetes. Obesity andinsulin resistance are associated with both impaired ANP and BNP cardiac release and over-expression of the clearance NPR-C, leading to reduced NP-mediated beneficial effects on targetorgans of metabolism (adipose tissue, skeletal muscle, pancreatic b-cells, central nervous sys-tem). This results in further weight gain and worsening of insulin resistance and also may favordiabetes development.

care.diabetesjournals.org Gruden, Landi, and Bruno 2905

them by enhancing active BNP produc-tion. In keeping with this scenario, re-cent data from the Multi-Ethnic Studyof Atherosclerosis (MESA) (81) haveshown that when subclinical CVD devel-ops and NT-proBNP levels rise, the in-verse relationship between NT-proBNPand both BMI and insulin resistance iscompletely lost.

FUTURE PERSPECTIVESIn the past decade our understanding ofthe role of the NP system in diabetes hassignificantly improved; however, manyquestions still need to be answered. Inparticular, more research is required toclarify the mechanisms of the natriuretichandicap in obesity, the pathogenetic linkbetween NP deficiency and diabetesonset, and the regulation of proBNPprocessing both in the heart and thebloodstream.Regarding the use of NPs for treat-

ment, preclinical and epidemiologicaldata support the hypothesis of a roleof ANP and BNP in the development ofobesity and diabetes, but it is still un-known whether ANP and BNP may beeffective in inducing weight loss andpreventing diabetes, and there are con-cerns that NP-induced excessive lipidmobilization may promote muscularand hepatic ectopic fat storage and,thus, insulin resistance. To address theseissues, development of appropriate ther-apeutic tools targeting the NP system andintervention trials in humans is neededand some effort has already been made.Studies looking at the effect of chronic NPinfusion on metabolism are ongoing (82)and long half-life BNP formulations areunder development (83). Agents that se-lectively either block NPR-C or activateNPR-A may be even more desirable asNPR-C overexpressionmay reduce the ef-ficacy of BNP infusion. An alternativestrategy is to enhance ANP andBNP levelsby inhibiting the catalytic enzyme NEP.However, NEP degrades other vasoactivepeptides, such as angiotensin I, bradyki-nin, and endothelin-1, leading to undesir-able hemodynamic effects. Combinedinhibition of NEP and ACE is not a suitablestrategy because of a significant in-creased risk of angioedema; however,the use of angiotensin receptor block-ade with NEP inhibition (ARNi) is apotential alternative option (23). Inthis regard, it is noteworthy that thePARADIGM-HF trial, testing efficacy

and safety of the ARNi LCZ696 as com-pared with enalapril in patients withHFREF (34% with diabetes), has beenstopped early based on evidence ofcompelling efficacy, and these prom-ising incoming results may open theway to future trials in obese anddiabetic patients.

Recent studies also suggest ancillaryeffects on the NP system of drugs cur-rently used for diabetes treatment. Inmice, liraglutide induces the cardiac re-lease of ANP. If results are confirmed inhumans, physicians may take advantageof this gut2heart link and use long-acting GLP-1 receptor agonists to com-pensate for NP deficiency and gainindirect beneficial hemodynamic andmetabolic effects mediated by ANP(45). DPP-4 inhibitors reduce BNP deg-radation to BNP3–32 (24) and thusmay enhance full-length BNP bioavail-ability, potentially resulting in advanta-geous effects. However, the SaxagliptinAssessment of Vascular OutcomesRecorded in Patients with DiabetesMellitus–Thrombolysis in MyocardialInfarction 53 (SAVOR-TIMI 53) trialhas unexpectedly shown increasedrates of hospitalization for HF in dia-betic patients treated with saxagliptin.Although treatment neither increasednor decreased the composite cardiovas-cular primary end point, further studiesare needed to clarify this issue and torule out the unlikely possibility of a BNP-related effect (84).

Finally, the use of more reliable andspecific assays for the measurement ofboth BNP and NT-proBNP is required.Although poor specificity of current as-says may not hamper the clinical valueof BNP and NT-proBNP as a predictorand biomarker of CVD, it significantlylimits our possibility to understandunderlying pathophysiological mecha-nisms and to envision novel therapeuticstrategies. Recently, a new antibodythat binds to the cleavage site of proBNP(Hinge76) has been developed, allowingaccurate proBNP measurement (85).Furthermore, new NT-proBNP assaysusing antibodies directed against non-glycosylated epitopes are under devel-opment to overcome the problem ofpoor reactivity of current assays forO-glycosylated NT-proBNP (25). Whetherthese new assays will result in betterclinical applicability awaits furtherevaluation.

CONCLUSIONS

Recent studies showing a role of NPs inmetabolism and T2Donset have extendedthe interest of NP-related research be-yond CVD and raised the possibility thatnew intervention strategies targeting theNP system may be effective in loweringnot only blood pressure and sodium re-tention but also body weight and the riskof diabetes. The use of NT-proBNP as atool for early diagnosis, risk assessment,and guided intervention in CVD holdsgreat promise for improving the care ofpatients with diabetes.

Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.

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