IJC Metabolic & Endocrine 2 (2014) 35–38

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IJC Metabolic & Endocrine

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Determinants of C-peptide levels and acute insulin resistance/sensitivity in nondiabeticSTEMI role of Killip class

Chiara Lazzeri ⁎, Serafina Valente, Maria Grazia D'Alfonso, Marco Chiostri, Gian Franco GensiniIntensive Cardiac Coronary Unit, Heart and Vessel Department, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy

⁎ Corresponding author at: Intensive Cardiac Care UnitViale Morgagni 85, 50134 Florence, Italy. Tel./fax: +39 55

E-mail address: lazzeric@libero.it (C. Lazzeri).

http://dx.doi.org/10.1016/j.ijcme.2014.02.0032214-7624/© 2014 The Authors. Published by Elsevier Ire

a b s t r a c t

a r t i c l e i n f o

Article history:Received 16 November 2013Received in revised form 2 February 2014Accepted 4 February 2014Available online 14 February 2014

Keywords:ST-elevation myocardial infarctionNondiabeticc-PeptideInsulinAcute insulin resistancePrognosis

The alterations in glucose homeostasis in the early phase of nondiabetic ST-elevation myocardial infarction(STEMI) are complex, involving not only hyperglycemia but also the development of acute insulin resistance(as part of the stress response) as assessed by the Homeostatic Model Assessment index (HOMA). No data isso far available on C-peptide values in the acute phase of STEMI in patients without previously known diabetes.The aims of the present investigation, performed in 782 consecutive STEMI patients without previously knowndiabetes, were as follows: a) to assess the determinants of C-peptide levels; b) to address the relation betweenacute insulin-resistance and Killip class; and c) to investigate the prognostic role of C-peptide for early mortality.In our series, 729 patients (93.2%) were in Killip I–II (group A), while 53 patients (6.8%) were in Killip classes III–IV (groupB). Group B showed higher levels of admission glycemia, insulin andC-peptide (pb 0.001, p= .022 andp b 0.001 respectively), together with higher values of HOMA-index and log-HOMA (p b 0.001 and p b 0.001,respectively) and reduced HOMA-%B (p = 0.014). Left ventricular ejection fraction was inversely correlatedwith C-peptide, insulin and admission glycemia (p b 0.001, p = 0.018 and p b 0.001, respectively). At logisticregression analysis C-peptide and insulin values were not associated with in-ICCU death.According to our data, the development of acute insulin resistance in the early phase of STEMI can be viewedas an adaptive mechanism to stress (represented by acute myocardial ischemia), similar to other acute criticalconditions, related to the severity of stress (that is to the hemodynamic impairment).

© 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Introduction

In the setting of acutemyocardial infarction [1], hyperglycemia is notsimply a marker of pre-existing diabetes or glucose intolerance but itmay represent a stress response to myocardial injury mainly related toacute catecholamine release [2,3]. In patients with ST elevationmyocar-dial infarction (STEMI) several studies addressed the glucose stressresponse [4] by investigating the prognostic role of glucose valuesmeasured on admission and throughout hospital stay [5–8].

However, the alterations in glucose homeostasis in the early phase ofSTEMI are far more complex, including also the development of acuteinsulin resistancewhich has been so far investigated only by few studiesby means of the Homeostatic Model Assessment (HOMA index) [9,10].No data is so far available on C-peptide values in the acute phase ofSTEMI in patients without previously known diabetes, taking intoaccount that C-peptide is a robust measure of insulin secretion but notof insulin action [11], differently from HOMA index.

, Heart and Vessel Department,7947518.

land Ltd. This is an open access articl

Since in critically ill patients the severity of insulin resistance isassociatedwith the severity of illness [12], we hypothesized that in non-diabetic STEMI patients advanced Killip classes were associated with amore severe acute insulin resistance.

The aims of the present investigation, performed in 782 consecutiveSTEMI patients without previously known diabetes, were as follows:a) to assess the determinants of C-peptide levels; b) to address therelation between acute insulin-resistance and Killip class; and c) toinvestigate the prognostic role of C-peptide for early mortality.

Methods

From 1st April 2009 to 31st December 2012, 782 consecutivepatients with STEMI (within 12 h from symptoms' onset) and withoutpreviously known diabetes were admitted to our Intensive CardiacCare Unit (ICCU), which is located at a tertiary center (where primarypercutaneous coronary intervention-PCI- can be performed 24/24 h7 days/week). In our hospital, in Florence, the reperfusion strategy ofSTEMI patients is represented by primary PCI [13–16]. After primaryPCI, they are admitted to our ICCU.

The diagnosis of STEMI was based on the criteria of the AmericanCollege of Cardiology/American Heart Association [13,16].

e under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Table 1Clinical characteristics.

All patientsAge (years), mean ± SD 65.5 ± 13.3

Males/Females, n (%) 578/204(73.9/26.1)BMI (Kg/m2), mean ± SD 26.1 ± 3.6History of, n (%)Smoking 506 (64.7)COPD 65 (8.3)Previous PCI 93 (11.9)Previous AMI 92 (11.8)Hypertension 347 (44.4)Comorbidities, n (%)0 71 (9.1)1–2 571 (73.0)N2 140 (17.9)

Charlson index (units),mean ± SD 1.0 (1.0–2.0)

1.67±1.26AMI location, n (%)anterior 393 (50.3)inferior 336 (43.0)Other 53 (6.8)Coronary artery disease, n (%)1-vessel 337 (43.1)2-vessel 278 (35.5)3-vessel 167 (21.4)Left main involvement, n (%) 44 (5.6)PCI failure, n (%) 38 (4.9)EF (%), mean ± SD 44.5 ± 9.3Time door-to-balloon (minutes),median (IR) 210 (150 to 300)

In-hospital mortality, n (%) 21 (2.7)

COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention;BMI: body mass index; AMI: acute myocardial infarction; LM: left main coronary artery;and EF: ejection fraction.

36 C. Lazzeri et al. / IJC Metabolic & Endocrine 2 (2014) 35–38

On ICCU admission, after PCI, in a fasting blood sample the followingparameters were measured: glucose (g/l), glycated hemoglobin (%),insulin (mU/l), C-peptide (mU/l), troponin I (Tn I, ng/ml), uric acid(mg/dl), NT-pro Brain Natriuretic Peptide (NT-pro BNP) (pg/ml), leuko-cytes count (∗103/μl), fibrinogen (mg/dl) and hs-C-Reactive proteinpositivity (hs-CRP) (normal values b 9). Intensive insulin therapy wasadministered in patients with significant hyperglycemia (that is plasmaglucose N 180 g/l) [4].

The presence of comorbidities was determined by taking thepatients' history directly and Charlson index was calculated [17].

Indexes of insulin-resistance/sensitivity

Criteria used for the definition of insulin resistance are in accordancewith the recently published guidelines proposed by the EuropeanGroupof the study of Insulin Resistance (EGIR) [18]. The Homeostatic ModelAssessment index (HOMA) was calculated according to the followingformula: {[fasting insulin (μU/ml)] × [fasting glucose (mmol/l)]}/22.5. Subjects whose values exceeded the sex-specific 75th percentile(i.e. 1.80 for women and 2.12 for men) were considered to have insulinresistance (HOMA-IR) [10,18]. Log (HOMA-IR) has been also calculatedsince it is considered useful for evaluation of insulin-resistance inindividuals with glucose intolerance, mild to moderate diabetes andother insulin-resistant conditions [19,20].

Beta-function has been evaluated by the following index [21]:HOMA-%B = (20 × FPI) / ((FPG-3.5) where FPI is the fasting plasmainsulin and FPG is the fasting plasma glucose [19,21–24].

Transthoracic 2-dimensional echo-cardiography was performed onICCU admission in order to measure left ventricular ejection fraction(LVEF).

The primary outcome was in-ICCU death.The study protocol was in accordance with the Declaration of

Helsinki and approved by the local Ethics Committee. Informed singedconsent was obtained in all patients before enrollment.

Statistical analysis

Data have been stored in a dedicated data-base and analyzed withIBM SPSS Statistics 20 for Microsoft® Windows® (SPSS-IBM, USA).Continuous data are reported as mean ± SD or median (interquartilerange, IR) as needed; comparisons between patients admitted in Killipclasses I–II and III–IV were performed by means of Student's t-test orMann–Whitney U-test, respectively. Categorical data are reported asfrequencies (percentages); between-group comparisons were madewith chi-square test. Correlations between some relevant anthropo-metric, clinic and laboratory data with admission glucose, insulin andC-peptide have been assessed with Spearman's rho. Logistic multivari-able regression analysis was used to investigate the impact of age,peak TnI, glucose, creatinine and C-peptide on in-ICCU death. Candidatevariables were chose as those considered relevant for the outcome,taking into account the number of events. Nevertheless, both modelsresulted slightly overfitted. Hosmer–Lemeshow goodness-of-fit testand Nagelkerke pseudo-R2 were reported for logistic models. Statisticalsignificance has been fixed at a two-tailed p value less than 5%.

Results

Table 1 depicts the clinical characteristics of the overall study popu-lation. In our series, the incidence of PCI was 4.9%, and in-ICCUmortalityand 1-year discharge mortality rates were 2.7 and 4.2%, respectively. Asshown in Table 2, 729 patients (93.2%) were in Killip I–II, while 53patients (6.8%) were in Killip classes III–IV. Patients in Group B showeda higher Charlson index (p b 0.001), more frequently anterior myocar-dial infarction (p= 0.041) and a 2-and 3-vessel coronary artery disease(p= 0.017), together with a higher incidence of PCI failure (p b 0.001)and a lower admission EF (p b 0.001). A higher in-ICCU mortality rate

was observed in Group B (p b 0.001). Higher values of Tn I, creatinine(admission, peak and discharge), NT-pro BNP, uric acid were observedinGroup B, togetherwith a higher inflammatory activation (as indicatedby increased values of leukocytes and CRP positivity). When comparedto patients in Group A, patients in Group B showed significantly higherlevels of admission glycemia, insulin and C-peptide (p b 0.001, p= .022and p b 0.001 respectively), together with higher values of HOMA-index and log-HOMA (p b 0.001 and p b 0.001, respectively) andreduced HOMA-%B (p = 0.014). No difference was observed in HbA1Cvalues between the two subgroups.

As shown in Table 3, LVEF was inversely correlated with C-peptide,insulin and admission glycemia (p b 0.001, p= 0.018 and p b 0.001, re-spectively). Similarly age showed an indirect correlationwith C-peptide,insulin and admission glycemia (p = 0.011, p = 0.073 and p b 0.001,respectively).

At logistic regression analysis (Table 4) C-peptide and insulin valueswere not associated with in-ICCU death.

Discussion

Homeostasis model assessment (HOMA), developed in 1985 [23], isa model of interactions between glucose and insulin dynamics that areused to yield an estimate of insulin sensitivity and beta-cell function[23]. The HOMA index assumes a feedback loop between the liver andbeta-cell [19–23]; i.e., the relation between glucose and insulin in thebasal state reflects the balance between hepatic glucose output andinsulin secretion [19,21]. Thus, deficient beta-cell function reflects adiminished response of beta-cell to glucose-stimulated insulin secre-tion. While the euglycemic hyperinsulinemic clamp is time consuming,labor intensive and requires an experienced operator to manage thetechnical difficulties, HOMA index is feasible in all clinical conditionsand information provided by this test is promptly available for

Table 2Clinical and laboratory data according to Killip class.

Killip classes I–IIn = 729, 93.2%Group A

Killip classes III–IVn = 53, 6.8%Group B

p value ⁎

t-test,Mann-Whitney U or χ2

Age (years), mean ± SD 65.2 ± 13.3 68.4 ± 12.6 0.090 tMales/females, n (%) 544/185

(74.6/25.4)34/19(64.2/35.8)

0.094 χ2

BMI (kg/m2), mean ± SD 26.2 ± 3.6 25.4 ± 4.0 0.129 tCharlson index (units),mean ± SD

1 (1–2)1.61 ± 1.22

2 (1–3)2.47 ± 1.41

b0.001 Ub0.001 t

AMI location, n (%) 0.041 χ2

Anterior 359 (49.2) 34 (64.2)Inferior 322 (44.2) 14 (26.4)Other 48 (6.5) 5 (9.4)

Coronary artery disease, n (%) 0.017 χ2

1-Vessel 324 (44.4) 13 (24.5)⁎2-Vessel 254 (34.8) 24 (45.3)3-Vessel 151 (20.7) 16 (30.2)

PCI failure, n (%) 33/723 (4.6) 10/53 (18.9) b0.001 χ2

EF (%), mean ± SD 45.4 ± 8.8 34.6 ± 9.8 b0.001 tTime door-to-balloon (minutes), median (IR) 210 (150–300) 210 (138–289) 0.726 UIn-hospital mortality, n (%) 9 (1.2) 12 (22.6) b0.001 χ2

Laboratory dataAdmission Glucose (g/l), median (IR) 1.23 (1.05 to 1.45) 1.62 (1.25 to 2.05) b0.001 UInsulin values (mU/l), median (IR) 8.7 (5.3 to 14.6) 12.4 (5.1 to 30.6) 0.022 UC-peptide values (mU/l), median (IR) 0.94 (0.64 to 1.27) 1.32 (0.88 to 2.26) b0.001 UHOMA index, median (IR) 0.47 (0.27 to 0.88) 0.83 (0.34 to 2.74) b0.001 ULog HOMA −0.21 ± 0.46 0.10 ± 0.54 b0.001HOMA-%B (insulin) 54.2 (33.9–80.6) 39.0 (20.9–77.9) 0.014HbA1c N 6.5%, n (%) 63 (8.6) 6 (11.3) 0.725 χ2

Tn I (ng/ml), median (IR) 79.2 (35.8–156.0) 221.0 (95.5–426.9) b0.001 UAdmission creatinine, median (IR) 0.90 (0.73–1.00) 1.10 (0.90–1.40) b0.001 UNT-proBNP (pg/ml) (n = 575), median (IR) 1079 (404–2508) 2620 (1279–11665) b0.001 UUric acid (mg/dl) (n = 668), mean ± SD 5.6 ± 1.6 6.3 ± 243 0.038 tESR (mm/h) (n = 708), median (IR) 20 (10–35) 26 (15–42) 0.097 ULeucocytes (1000 counts/μl), median (IR) 10.5 (8.5–13.1) 13.3 (10.0–19.2) b0.001 UCRP positivity (%), n (%) 351(48.2) 38 (71.6) 0.008 χ2

Fibrinogen (mg/dl), mean ± SD 409 ± 107 410 ± 126 0.983 t

MI: acute myocardial infarction, HOMA: Homeostatic Model Assessment; BMI: body mass index; EF: ejection fraction; PCI: percutaneous coronary intervention; NT-pro-BNP: N terminalpro Brain Natriuretic Peptide; ESR: erythrocyte sedimentation rate; and CRP: C-Reactive Protein;⁎ t: at Student's t-test; χ2: at chi-square test; U: at Mann–Whitney U-test.

Table 4Logistic regression analysis.

Adjusted OR 95% CI p value

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clinicians. HOMA index has been recently used to estimate insulin resis-tance in critically ill patients with acute renal failure [25] as well as incritically ill medical patients [26,27] and we recently [10] documentedthat, in the acute phase of STEMI, HOMA index represented an indepen-dent predictor of in-hospital mortality in 253 nondiabetic STEMI pa-tients submitted to PCI. In our series, insulin resistance, as assessed byHOMA index, was quite common, as it affected half of the population,and was associated with a larger infarct size (as inferred by highervalues of cardiac enzymes) and more severe metabolic derangements(as indicated by N-terminal-proBNP and lactic acid levels) [10]. In asmall cohort of 79 STEMI patients [26], patients in Killip classes II–IV(32 patients) showed higher values of C-peptide and intensive insulin

Table 3Correlations (Spearman's Rho).

C-peptide Insulin Adm. glucose

C-peptide – 0.57, p b 0.001 0.27, p b 0.001Insulin 0.57, p b 0.001 – 0.26, p b 0.001Glycemia 0.27, p b 0.001 0.26, p b 0.001 –

Age −0.09, p = 0.011 −0.07, p = 0.073 0.22, p b 0.001BMI 0.23, p b 0.001 0.28, p b 0.001 0.05, p = 0.141LVEF −0.16, p b 0.001 −0.10, p = 0.018 −0.21, p b 0.001Peak Tn I 0.17, p b 0.001 0.16, p b 0.001 0.18, p b 0.001Creatinine 0.41, p b 0.001 0.11, p = 0.009 0.17, p b 0.001Leukocytes 0.15, p b 0.001 0.20, p b 0.001 0.26, p b 0.001Hb A1c 0.09, p = 0.027 0.14, p b 0.001 0.27, p b 0.001

BMI: body mass index, LVEF: left ventricular ejection fraction; and Tn I: troponin I.

resistance (as inferred by QUICKI index [20]) in respect to patients inKillip I and controls, respectively.

In the present investigation, we addressed, for the first time, the“acute insulin-resistance phenomenon” in the early phase of STEMI in abroader way, by evaluating beta-cell secretion (by means of C-peptide)and function (by means of HOMA-%B index) and insulin action (as indi-cated by HOMA index).

Model 1Age (1 year step) 1.05 1.00–1.10 0.034Peak Tn I (10 ng/ml step) 1.04 1.02–1.06 b0.001Adm. glucose (1 g/dl step) 5.42 2.84–10.35 b0.001Creatinine (1 mg/dl step) 1.48 0.78–2.81 0.236

Model 2Age (1 year step) 1.05 1.00–1.10 0.037Peak Tn I (10 ng/ml step) 1.04 1.02–1.06 b0.001Adm. glucose (1 g/dl step) 5.40 2.77–10.53 b0.001Adm. creatinine (1 mg/dl step) 1.47 0.77–2.82 0.240C-peptide (1 mU/l step) 1.00 0.86–1.18 0.966

Model 3Age (1 year step) 1.04 0.99–1.08 0.121Peak Tn I (10 ng/ml step) 1.05 1.03–1.07 b0.001Insulin (1 mU/l step) 1.00 0.99–1.01 0.998Creatinine (1 mg/dl step) 1.65 1.03–2.65 0.038C-peptide (1 mU/l step) 1.02 0.94–1.11 0.557

Hosmer–Lemeshow goodness-of-fit test χ2 5.1, p = 0.742; and Nagelkerke pseudo-R2

0.30.

38 C. Lazzeri et al. / IJC Metabolic & Endocrine 2 (2014) 35–38

In our series, C-peptide values are inversely related to LVEF (andsignificantly higher in advanced Killip class) thus indicating an intensestimulation of Beta-cell secretion in conditions of hemodynamic impair-ment which are further characterized by a high degree of insulin resis-tance (as indicated by higher values of HOMA index and log-HOMA)and a reduced beta-cell function (as inferred by reduced values ofHOMA-%B index). Our findings can be strictly related to the acute stressresponse since no difference was observed in glycated hemoglobinbetween the two Killip class subgroups.

In our investigation, we further confirm that acute glucose metabo-lism is affected by age in the early phase of STEMI, since glucose, insulinand C-peptide values were inversely related to age [28].

According to our data, the development of acute insulin resistance inthe early phase of STEMI can be viewed as an adaptive mechanism tostress (represented by acute myocardial injury) which is similar toother acute critical conditions (such as trauma, post surgery state, med-ical critical illness) [29] and which is related to the severity of stress(that is to the hemodynamic impairment). The finding that C-peptideand insulin values cannot be related to in-ICCU death is in agreementwith the concept that they are part of an adaptive mechanism.

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