Open Access

Hyperinsulinemia improves ischemic LV function in insulin resistant subjects

  • Patrick M Heck1,
  • Stephen P Hoole1,
  • Sadia N Khan2 and
  • David P Dutka1Email author
Cardiovascular Diabetology20109:27

DOI: 10.1186/1475-2840-9-27

Received: 7 April 2010

Accepted: 24 June 2010

Published: 24 June 2010

Abstract

Background

Glucose is a more efficient substrate for ATP production than free fatty acid (FFA). Insulin resistance (IR) results in higher FFA concentrations and impaired myocardial glucose use, potentially worsening ischemia. We hypothesized that metabolic manipulation with a hyperinsulinemic euglycemic clamp (HEC) would affect a greater improvement in left ventricular (LV) performance during dobutamine stress echo (DSE) in subjects with IR.

Methods

24 subjects with normal LV function and coronary disease (CAD) awaiting revascularization underwent 2 DSEs. Prior to one DSEs they underwent an HEC, where a primed infusion of insulin (rate 43 mU/m 2/min) was co-administered with 20% dextrose at variable rates to maintain euglycemia. At steady-state the DSE was performed and images of the LV were acquired with tissue Doppler at each stage for offline analysis. Segmental peak systolic velocities (Vs) were recorded, as well as LV ejection fraction (EF). Subjects were then divided into two groups based on their insulin sensitivity during the HEC.

Results

HEC changed the metabolic environment, suppressing FFAs and thereby increasing glucose use. This resulted in improved LV performance at peak stress, measured by EF (IS group mean difference 5.3 (95% CI 2.5-8) %, p = 0.002; IR group mean difference 8.7 (95% CI 5.8-11.6) %, p < 0.0001) and peak V s in ischemic segments (IS group mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR group mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001) , that was greater in the subjects with IR.

Conclusions

Increased myocardial glucose use induced by HEC improves LV function under stress in subjects with CAD and IR. Cardiac metabolic manipulation in subjects with IR is a promising target for future therapy.

Background

Insulin increases myocardial glucose utilization and reduces free fatty acid (FFA) oxidation via several mechanisms[14]. Glucose oxidation is more oxygen efficient than FFA oxidation[5], hence this change in myocardial metabolism is theoretically beneficial to the heart[5], especially during ischemia, and is thought to be the main mechanism behind the beneficial effects seen in the various trials of glucose-insulin-potassium infusions[68].

The presence of insulin resistance (IR) or type 2 diabetes has been shown to affect the metabolic pathway of glucose at multiple levels, from uptake into the myocyte, through to final oxidation within the mitochondria. It has long been known that the subjects with IR are at much greater risk of heart failure and death when compared to insulin sensitive (IS) subjects and these differences cannot be accounted for by other risk factors such as hypertension and vascular disease[9, 10].

We hypothesized that altering the myocardial metabolic environment, by creating hyperinsulinemia whilst maintaining euglycemia, would improve ischemic left ventricular function during dobutamine stress in subjects with known coronary artery disease (CAD) and that this effect would be greater in IR subjects.

Methods

Subjects

Consecutive subjects with angiographically normal left ventricular (LV) function and symptomatic CAD, awaiting revascularization of stenoses ≥ 75%, were invited to participate. Recruitment was carried out over an 18 month period from a tertiary referral centre for cardiology. Exclusion criteria included LV ejection fraction (EF) of < 40% (either on echocardiography or LV angiography), type 2 diabetes mellitus receiving insulin therapy, significant valvular heart disease, atrial fibrillation, permanent pacemakers or severe co-morbidities. The study had ethical approval from the Local Research Ethics Committee and all subjects gave written informed consent before participating. The study conformed with the principles set out in the Helsinki Declaration.

Study design

Each subject underwent two dobutamine stress echocardiograms (DSEs) one week apart, thereby acting as their own controls. Both scans were performed before subjects underwent their planned revascularization. One DSE, determined randomly, was performed during the steady-state phase of a hyperinsulinemic, euglycemic clamp (HEC).

Dobutamine stress echocardiography

Subjects attended for both studies after an overnight fast and their beta-blocker therapy was withheld for 48 hours prior to their attendance. Any oral hypoglycemic agents were stopped 12 hours prior to the studies. After acquiring the resting images, dobutamine was infused intravenously via the antecubital fossa at a starting dose of 10 mcg/kg/min and increased every 3 minutes to doses of 20, 30 and 40 mcg/kg/min. Up to 1.2 mg of atropine, in doses of 300 mcg, was given to subjects who had not reached target heart rate (85% of predicted maximum heart rate) or any other end-point. Subjects underwent continuous 12-lead ECG monitoring, with blood pressure being recorded at baseline and at the end of each stage of dobutamine.

Standard clinical endpoints were used, including intolerable symptoms (such as chest pain), > 2 mm of planar or down-sloping ST-segment depression, persistent arrhythmias such as ventricular tachycardia or atrial fibrillation, and hypotension (a fall of systolic pressure 30 mmHg) or bradycardia.

Image acquisition

All echocardiographic images were obtained with a standard, 2D echocardiography system (Vivid Seven, GE Medical Systems) and stored digitally. Standard apical views of the LV were acquired at rest and at each stage of dobutamine stress with the patient in the left recumbent position. To minimize beat-to-beat variability, all recordings were made in gently held end-expiration and stored for subsequent off-line analysis (Echo PAC PC software, GE Medical Systems).

Analysis

An expert observer blinded to the clinical data and tissue Doppler results performed all the echocardiographic analyses. The ejection fraction (EF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were calculated from the apical views using the modified Simpson's biplane method[11]. From these measurements, stroke volume (SV) and cardiac output (CO) were then also calculated.

Tissue Doppler imaging

Acquisition

Color tissue Doppler imaging (TDI) was used to assess longitudinal myocardial tissue velocities and myocardial strain generation at baseline and each stage of dobutamine stress. The filter was set to exclude high frequency signal, and the Nyquist limit was set to 24 cm/s to minimize aliasing during stress. The sector angle and imaging depth were minimized to maintain adequate frame rates of at least 140 frames per second.

Analysis

Off-line analysis was performed by one observer, blinded to the nature of the study. A 6 × 6 mm sampling area was applied to the annulus, basal and mid segments of each wall of the LV. Apical segments were not analyzed for velocity because off-line velocities in these segments have been shown to be unreliable[12]. Analysis of myocardial strain was performed on all 16 LV segments. A 6 by 12 mm sample area was placed in the middle of each segment. It was then tracked semi-automatically throughout each cardiac cycle to ensure that it remained in the middle of the segment and did not sample the LV blood pool. Peak systolic (Vs) velocity and post-systolic strain (PSS) were recorded from 3 beats and averaged for each sample point. These measurements were chosen as they have been shown to be the more sensitive and reproducible TDI markers of ischemia in DSE[1216]. The intraobserver and interobserver variability for TDI measurements in our intuition are 11% and 17% respectively.

The LV segments were classified as either 'ischemic' or 'non-ischemic' on the basis of the anatomy of the subject's coronary artery disease and the predicted arterial blood supply to each segment, based on the guidelines from the ASE[17].

Hyperinsulinemic, euglycemic clamp

A hyperinsulinemic euglycemic clamp was performed as described previously[18]. After patients had fasted overnight, a cannula was inserted into a vein in the antecubital fossa for infusion of glucose and insulin. A second cannula was inserted in the opposite arm, which was arterialized using a heating pad set at 50°C. After an initial loading dose, insulin (Human Actrapid, Novo Nordisk) was infused at a constant rate of 43 mU/min/m 2 of body surface area. Blood glucose levels were sampled every 5 to 10 minutes from the opposite cannula and analyzed using the glucose oxidase method (YSI 2300, YSI Life Sciences, Ohio). Glucose infusion rates were adjusted accordingly, with the aim of maintaining constant glucose levels[18]. Once steady state was achieved, as indicated by 3 consecutive blood glucose values that were within 5% of one another, the subjects underwent DSE as described above. The insulin infusion was stopped at the end of the peak dobutamine stress stage, along with the dobutamine infusion, but the glucose continued for an additional 20 minutes to avoid rebound hypoglycemia.

Assessment of insulin resistance

The glucose clamp technique, originally developed by DeFronzo et al.[18], is widely accepted as the reference standard for directly determining metabolic insulin sensitivity in humans[19]. After at least one hour of constant insulin infusion, steady-state conditions can typically be achieved for plasma insulin, blood glucose and the glucose infusion rate. It is assumed that the hyperinsulinemic state is sufficient to completely suppress hepatic glucose production. Accordingly, since there is no net change in blood glucose concentrations under steady-state clamp conditions, the glucose infusion rate must be equal to the glucose disposal rate, and this value is termed M-value. Thus, whole body glucose disposal at a given level of hyperinsulinemia can be determined directly. M-value is typically normalized to body weight or fat-free mass to generate an estimate of insulin sensitivity (mg/kg/min).

Biochemical analysis

In addition to blood glucose sampling, serum insulin, c-peptide (both using commercially available AutoDELFIA Automatic Immunoassay kits, PerkinElmer, Waltham, MA) and FFA (modified Roche Free Fatty Acid enzymic colorimetric kit assay) concentrations were measured at baseline, steady state (pre-DSE), peak stress and 30 minutes into recovery during the clamped study and also at baseline, peak stress and 30 minutes into recovery of the control (unclamped) study.

The coefficients of variation for the insulin assay ranges from 3.1% at 29 pmol/l to 1.9% at 277 pmol/l. For the c-peptide assay: 4.8% at 472 pmol/l to 3.7% at 2056 pmol/l and for the FFA assay: 10.6% at 112 μmol/l and 4.3% at 465 μmol/l.

Statistical analysis

The primary outcome for the study was LV EF. The study had a 90% power to detect an absolute improvement in EF of 5% in the clamp versus the control group with a significance level of 0.05. The analyses were restricted to the 24 patients who had both control and clamped studies. Descriptive summaries are expressed as the mean (standard deviations) for continuous measurements and as the number (percentage) for categories. Comparisons between control and clamped measurements were made using paired Student's t-tests. Comparison between different stages of the clamp were done by the ANOVA method. Fisher's exact test was used to compare the incidence of PSS in the control and clamp study. The statistical software programs SPSS 12.0.1 (SPSS, Cary, NC) was used for the statistical analyses.

Results

Twenty-six subjects were recruited of whom 24 completed the study. One subject was unable to complete the study due to emergency admission with unstable angina, and one subject withdrew consent. The median M-value for the 24 subjects was 3.2 mg/kg/min. The subjects were thus divided into two groups; those with an M-value less than 3.2 mg/kg/min (the insulin resistant (IR) group) and those with an M-value greater then 3.2 mg/kg/min (the insulin sensitive (IS) group). The demographics for the two groups are shown in Table 1. There were no differences between the two groups except for weight.
Table 1

Demographics of IS and IR groups

Parameters

Insulin Sensitive (IS)

Insulin Resistant (IR)

P

Age

64 (8)

64.2 (8)

ns

Male, n (%)

11 (92)

10 (83)

ns

Medication, n (%)

   

β-Blocker

11 (92)

11 (92)

ns

Nitrate

9 (75)

6 (50)

ns

Calcium Channel Blocker

2 (17)

3 (25)

ns

Statin

12 (100)

11 (92)

ns

Ejection Fraction, %

62.2 (4)

63.3 (6)

ns

Coronary Disease, n (%)

   

LAD stenosis

6 (50)

10 (83)

ns

LCx stenosis

4 (33)

3 (25)

ns

RCA stenosis

5 (42)

5 (42)

ns

Single vessel CAD

10 (83)

8 (67)

ns

Two vessel CAD

1 (8)

2 (17)

ns

Three vessel CAD

1 (8)

2 (17)

ns

Weight (Kg)

82 (15)

97.5 (20)

0.04

BSA (m2)

1.96 (0.2)

2.1 (0.2)

ns

M Value (mg/kg/min)

5.7 (1.3)

2.2 (0.7)

< 0.0001

Diabetes* n (%)

3 (25)

6 (50)

ns

   Diet controlled

3 (25)

2 (17)

ns

   Metformin

0

3 (25)

ns

   Metformin and sulphonyl urea

0

1 (25)

ns

BSA = body surface area. * = subjects with a clinical diagnosis of type 2 diabetes receiving oral hypoglycemic agents. Ns = not significant

Dobutamine stress

The dose of dobutamine and atropine administered in each group were similar. This equivalent level of pharmacological stress resulted in heart rates (HRs), systolic blood pressures (SBPs) and rate pressure products (RPPs) that did not differ significantly between the control and clamped scans at peak dobutamine stress in either the IS or IR group (Table 2). There were no differences between the IS and IR groups in the hemodynamic response shown with dobutamine stress in both control and clamped studies.
Table 2

Peak HR, blood pressure and RPP during DSE in IS and IR groups

  

Insulin Sensitive

Insulin Resistant

  

Control

Clamp

p

Control

Clamp

p

Max Dobutamine dose (μg/kg/min)

37.5 (4.5)

38.3 (3.9)

ns

35.8 (5.1)

35 (5.2)

ns

Mean Atropine dose (μg)

150 (239)

150 (239)

 

100 (233)

100 (233)

 

Hemodynamic variables

      

Mean %max HR achieved

83 (8)

83 (5)

ns

81 (7)

80 (9)

ns

Peak

HR (bpm)

130 (15)

130 (10)

ns

126 (10)

124 (13)

ns

 

SBP (mmHg)

147 (21)

143 (20)

ns

142 (25)

141 (25)

ns

 

RPP (bpm.mmHg)

19026 (2850)

18554 (2925)

ns

17897 (3298)

17540 (3979)

ns

Ns = not significant

Biochemical analyses

The metabolic responses of both groups during the clamp are shown in Table 3 and Figure 1.
Table 3

Metabolic parameters for clamp studies

Glucose (mg/dl)

Insulin Sensitive

Insulin Resistant

p

C-peptide (pmol/l)

Insulin Sensitive

Insulin Resistant

p

Baseline

88 (14)

104 (27)

0.07

Baseline

683 (291)

1251 (352)

0.001

Steady state

86 (11)

106 (13)

0.0004

Steady state

493 (219)

1124 (361)

0.0002

Peak Stress

88 (11)

106 (11)

0.0004

Peak Stress

804 (334)

1465 (524)

0.004

Recovery

93 (18)

106 (20)

ns

Recovery

836 (363)

1374 (646)

0.04

Insulin (pmol/l)

   

FFA (nmol/l)

   

Baseline

38.9 (18.7)

102 (27.6)

< 0.0001

Baseline

374 (153)

548 (299)

ns

Steady state

447 (78.6)

624 (150)

0.004

Steady state

49.2 (51.3)

114 (72)

0.04

Peak Stress

386 (82.9)

523 (198)

0.06

Peak Stress

365 (160)

374 (113)

ns

Recovery

90.1 (45.3)

174 (117)

0.05

Recovery

83.9 (79.1)

197 (52.1)

0.002

FFA = free fatty acids. Ns = not significant

https://static-content.springer.com/image/art%3A10.1186%2F1475-2840-9-27/MediaObjects/12933_2010_Article_246_Fig1_HTML.jpg
Figure 1

Metabolic parameters during control and clamped studies. shows the glucose, c-peptide, FFA and insulin concentrations during control, graphs (a), left, and clamped studies, graphs (b), right. The black square represents the IS group and the white circle the IR group. Numbers plotted are mean values and the standard errors. Detailed description of the results is in the main text. * = p < 0.05; ** = p < 0.01 for comparison between IS and IR group.

C-Peptide

The c-peptide concentrations were significantly higher in the IR groups at every stage of the clamp.

Glucose

The baseline glucose concentration in the IS group was lower than in the IR group (88 (14) vs. 104 (27) mg/l, p = 0.07), although this did not achieve statistical significance. At both the steady state and peak DSE stages of the clamp, the difference in the glucose concentration in the IS group did achieve statistical significance.

Insulin

Baseline fasted insulin concentration in the IS group was significantly lower than the IR group (38.9 (18.7) vs. 102 (27.6) pmol/l, p < 0.0001). Although there is considerable overlap in insulin concentrations between normal and insulin resistance, a fasting serum insulin concentration of greater than the upper limit of normal for the assay used (approximately 60 pmol/l) has been considered a marker of insulin resistance[20, 21] and this supports the separation of the subjects into IS and IR groups using M value. This trend in lower insulin concentration in the IS groups was present at every stage of the clamp, although it did not achieve statistical significance at the peak DSE or recovery stages.

FFA

The HEC resulted in more marked suppression of free fatty acid production in the IS group, resulting in a significantly lower FFA concentration at steady state. This difference was negated by the profound lipolytic effect of dobutamine at peak stress, but was again present in the recovery stage.

2D echo measurements

The LV volumes, EF and CO are shown in Table 4. Measurements were made just prior to commencing the dobutamine infusion ('Pre-DSE'), at peak dobutamine stress ('Peak') and 15 minutes after stopping the dobutamine infusion ('Recovery').
Table 4

2D echocardiographic measurements

Echocardiographic variables

Insulin Sensitive

Insulin Resistant

  

Control

Clamp

p

Control

Clamp

p

Pre-DSE

EDV (ml)

102

(16)

99.2

(19)

ns

108

(24)

103

(27)

ns

 

ESV (ml)

38.6

(7)

36

(9)

ns

40.1

(13)

37.5

(13)

ns

 

SV (ml)

63.6

(11)

63.2

(13)

ns

68

(15)

65.4

(15)

ns

 

CO (L/min)

3.7

(0.4)

3.6

(.7)

ns

4.2

(1.1)

4

(1.1)

ns

 

EF (%)

62.2

(4)

63.8

(4.5)

ns

63.3

(6)

64.3

(5.9)

ns

Peak

EDV (ml)

74.9

(14)

74.8

(16)

ns

86.1

(22)

93.3

(28)

ns

 

ESV (ml)

26.4

(9)

22.1

(7)

0.09

31.3

(14)

25.4

(11)

0.03

 

SV (ml)

48.5

(8)

52.6

(12)

ns

54.8

(11)

68

(19)

0.003

 

CO (L/min)

6.3

(1.4)

6.8

(1.7)

ns

6.9

(1.5)

8.3

(2.1)

0.001

 

EF (%)

65.2

(6.1)

70.4

(6.3)

0.002

64.8

(7.2)

73.5

(5.8)

< 0.0001

Recovery

EDV (ml)

92.2

(21)

98.7

(21)

ns

103

(24)

104

(23)

ns

 

ESV (ml)

35.5

(11)

39

(11)

ns

40.5

(15)

35.8

(13)

0.09

 

SV (ml)

56.6

(13)

58.7

(12)

ns

62

(12)

68

(12)

0.05

 

CO (L/min)

4.4

(0.8)

4.7

(0.8)

ns

4.7

(0.8)

5

(1)

ns

 

EF (%)

61.8

(5.9)

60.4

(4.5)

ns

61.5

(7.5)

66.4

(6.7)

0.03

Ns = not significant

Ejection fraction

The pre-DSE EF were unaffected by the clamp in both groups. At peak stress the clamp significantly improved the EF in both the IS group mean improvement 5.3% (95% CI 2.5 to 8), p = 0.002; IR group mean difference 8.7% (95% CI 5.8 to 11.6), p < 0.0001), with a larger magnitude effect in the IR group. At the recovery stage, the clamp continued to have a positive effect on the IR group (mean improvement 4.8% (95% CI, 0.7 to 8.9), p = 0.03), but not in the IS group (mean improvement 1.4% (95% CI, -2.1 to 5), p = 0.4).

EDV

There was no significant effect of HEC on EDV in either IS or IR groups at any stage.

ESV

At peak dobutamine stress the ESV was significantly reduced in the clamp study in the IR group (mean difference 5.9 (5.3) mls, p = 0.03). There was a reduction in the ESV of the IS group at peak stress, but the magnitude of effect was smaller than in the IR group and it did not achieve statistical significance (mean difference 4.3 (5) mls, p = 0.09).

SV and CO

At the pre-DSE stage the clamp exerted no effect on either SV or CO in either group. At peak stress both SV and CO were significantly improved in the IR group (SV mean difference 13.1 (8) mls, p = 0.003; CO mean difference 1.4 (0.7) l/min, p = 0.001), but not in the IS group (SV mean difference 4.2 (7) mls, p = 0.2; CO mean difference 0.5 (1) l/min, p = 0.3). There were no significant differences in the SV and CO in the recovery stage.

Tissue Doppler imaging

Peak dobutamine Vs

The results for the peak Vs are shown in Table 5. Paired tissue Doppler systolic velocities (Vs) were recordable in 94.4% (272 out of 288) at peak dobutamine. The Vs velocities were consistently higher for all segments in the clamped studies, but it was only in the IR group that this improvement achieved statistical significance, and it was most significant in the segments classified as ischemic (IS ischemic segments mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR ischemic segments mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001).
Table 5

Mean segmental Vs at peak dobutamine stress

 

Insulin Sensitive

Insulin Resistant

 

Control

Clamp

n

p

Control

Clamp

n

p

Annulus points

10.6 (2.5)

10.9 (2.3)

72

ns

9.0 (3.3)

10.0 (3.0)

66

0.002

Ischemic segments

8.6 (4.0)

9.3 (4.2)

57

0.07

5.9 (3.1)

6.7 (2.8)

66

< 0.0001

Non-ischemic seg.

8.4 (3.4)

8.5 (3.0)

82

ns

7.3 (3.4)

8.3 (3.6)

67

0.02

n = number of paired values used for analysis. Ns = not significant.

Post systolic strain (PSS)

The incidences of PSS at baseline and the development of new PSS at peak stress and recovery are shown in Table 6. The incidence of PSS at baseline was similar in each group are compares well to the reported incidence of PSS in normal myocardium[14]. At peak DSE and in recovery in both groups the clamp resulted in fewer segments exhibiting new PSS (i.e. segments that did not have PSS at baseline), but this effect was most marked, and achieved statistical significance, in the recovery stage in the IR subjects (15 segments in the clamp vs. 30 in the control, p = 0.03), suggesting less post-ischemic dysfunction.
Table 6

Number of myocardial segments with post systolic strain (PSS)

 

Insulin Sensitive

Insulin Resistant

Baseline PSS

Control

Clamp

p

Control

Clamp

p

Ischemic

21 (25)

27 (32)

ns

36 (31)

44 (38)

ns

Non-ischemic

30 (28)

31 (29)

ns

24 (32)

22 (30)

ns

New PSS at Peak Stress

Ischemic

31 (48)

26 (45)

ns

40 (49)

34 (47)

ns

Non-ischemic

40 (52)

30 (39)

ns

20 (39)

22 (42)

ns

New PSS in Recovery

Ischemic

21 (33)

16 (28)

ns

30 (37)

15 (21)

0.03

Non-ischemic

29 (38)

25 (33)

ns

11 (22)

6 (12)

ns

Data shown is n (%). Ns = not significant.

Discussion

This study shows that in subjects with flow-limiting CAD alteration of myocardial substrate utilization improves LV function during DSE in both IR and IS subjects and lessens post-ischemic dysfunction in IR subjects. Whilst similar effects were seen in both groups, the magnitude was less in the IS group and so it did not generally achieve statistical significance in this study. Overall, though, the effects are fairly modest and whilst the sample size is small, the improvements observed in the clamped DSE in IR group, in particular the reduction in post-ischemic dysfunction are likely to have clinical significance.

Left ventricular performance during stress

Euglycemic hyperglycemia during DSE significantly improved the primary endpoint of LV EF at peak stress in both IS and IR groups. Whilst the LV EF was significantly improved by the HEC in the IS group, it was the only one of the indices of LV function that was significantly improved. Peak stress SV, ESV, CO and Vs were slightly increased in the IS group, but not significantly so. Whereas, in the IR group at peak stress SV, ESV, CO and Vs were all significantly improved.

The improvements in the IR group were not limited to the peak systolic function. Post-systolic thickening or strain is a well reported and sensitive marker of stunning[2227]. In the IS group the clamp tended to result in fewer segments with PSS in the recovery stage, but the difference was not statistically significant. In the IR group, however, the effect was far more pronounced and statistically significant, with almost half as many segments exhibiting PPS in the recovery stage of the clamp compared to the control.

Metabolic environment

As expected, baseline metabolic profiles of the two groups were different, with the IR group having higher insulin and c-peptide concentrations. The FFA and glucose concentrations were also elevated in the IR group, but not significantly so, due in part to the sub-study being relatively underpowered to assess these. These differences are expected, as the groups were not randomly selected, but selected on the basis of each subject's insulin sensitivity, measured during the HEC. Elevated fasting glucose, insulin and FFA concentrations are all part of the phenotype seen in insulin resistance[20, 28].

At the steady state phase of the clamp, before the start of the dobutamine stress, the differences in the metabolic measurements persisted. Despite the higher insulin concentration in the IR group, lipolysis inhibition was not as complete, with a persisting elevation of the FFA concentration compared to the IS group. As one of the main driving forces for myocardial FFA uptake and utilization is substrate availability[29, 30], it would therefore be expected that the myocardium in the IR groups will be using more FFAs than in the IS group and that this might disadvantage the IR group.

Possible mechanisms

Whilst the metabolic environment just prior to commencing the dobutamine stress may not have been as well optimized in the IR group as the IS group, with presumed higher FFA use and lower glucose use, it is apparent that the improvement in LV performance during DSE seen with the clamp in the IR group was greater than that observed in the IS group. There are several possible reasons to explain this, of which all or none may contribute.

The normal myocardial response to ischemia is to increase glucose uptake, glycogenolysis and glycolysis[31], as well as increase FFA oxidation[32]. Perhaps, in insulin sensitive individuals, challenged with only modest amounts of myocardial ischemia as in this study, this intrinsic metabolic switch is adequate and additional stimulation of glucose oxidation with the HEC provides minimal incremental benefit in this group, whereas in the IR group this intrinsic metabolic switching mechanism is impaired but can be overcome with the HEC.

Also, insulin resistance has been shown to have several adverse effects on the metabolism of the myocardium that heighten the effects of ischemia. These include reduced glucose uptake[3335] and oxidation[36], increased FFA uptake and oxidation[37, 38] as well as decrease in calcium transport within the sarcolemma and alterations in myofibrillary regulatory contractile proteins[39]. The net effect is a reduction in cardiac efficiency[40] at rest that may predispose to diabetic cardiomyopathy[4143], but that also causes increases the susceptibility of the insulin resistant heart to myocardial ischemia and to a greater reduction in myocardial performance for a given amount of ischemia compared with the normal heart[4446]. It therefore stands to reason that insulin resistant myocardium has far more to gain by optimization of its metabolism, so provided the hyperinsulinemia generated by the clamp is sufficient to overcome the IR, then the improvement in myocardial performance during and after ischemia will be greater than in IS subjects.

An alternative explanation is the improved LV performance observed in the IR group may be accounted for by the elevated glucose and insulin concentration present throughout the clamp stimulating greater myocardial glucose uptake, compared to the IS group. However, work by others has shown that subjects with IR can have impaired glucose uptake compared to IS subjects, even during hyperinsulinemia[47, 48], making the additional hyperinsulinemia seen in the IR subjects in this study unlikely to result in significantly greater myocardial glucose uptake compared to the IS subjects, although this cannot be proved.

Study limitations

The most significant limitation of this study is the sample size. The study was powered to assess EF, which was improved in both groups, and it may have been underpowered to assess some of the other variables. It is possible, therefore, that some of the TDI variables that were not significantly different in the IS group, but showed trends of improvement with the clamp, failed to achieve significance due to a lack of power.

Another limitation of this study is use of quantative QCA to define ischemic myocardial segments as opposed to functional imaging such as myocardial perfusion SPECT. Subjects will have variable coronary anatomy and functional imaging would be better as assessing which segments were ischemic.

Also, a number of assumptions on myocardial metabolism and the effect the HEC has on this have had to be made. Direct measurement of myocardial substrate metabolism is challenging, requiring a combination of arterial and coronary sinus venous blood sampling or sophisticated PET imaging with radio-labeled substrates such as glucose and palmitate[49, 50]. However, previously-reported work by others has investigated the effects of HEC on myocardial metabolism in humans[51, 52], so the assumptions are evidence-based.

Conclusions

This study shows that hyperinsulinemic euglycemia during DSE improves LV function in both IR and IS subjects with flow-limiting coronary disease. It also suggests that subjects with IR may benefit more in terms of increased cardiac performance and reduced post-ischemic dysfunction compared insulin sensitive subjects.

Declarations

Acknowledgements

PMH, SPH and SNK all received funding from the British Heart Foundation.

Authors’ Affiliations

(1)
Cardiovascular Medicine, ACCI, Level 6, Addenbrooke's Hospital
(2)
Department of Cardiology, Papworth Hospital, Papworth Everard

References

  1. Young LH, Coven DL, Russell RR: Cellular and molecular regulation of cardiac glucose transport. J Nucl Cardiol. 2000, 7: 267-276. 10.1016/S1071-3581(00)70016-X.View ArticlePubMed
  2. Lawson JW, Uyeda K: Effects of insulin and work on fructose 2,6-bisphosphate content and phosphofructokinase activity in perfused rat hearts. J Biol Chem. 1987, 262: 3165-3173.PubMed
  3. Hall JL, Henderson J, Hernandez LA, Kellerman LA, Stanley WC: Hyperglycemia results in an increase in myocardial interstitial glucose and glucose uptake during ischemia. Metabolism. 1996, 45: 542-549. 10.1016/S0026-0495(96)90022-0.View ArticlePubMed
  4. Taegtmeyer H: Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol. 1994, 19: 59-113. 10.1016/0146-2806(94)90008-6.View ArticlePubMed
  5. Liedtke AJ: Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis. 1981, 23: 321-336. 10.1016/0033-0620(81)90019-0.View ArticlePubMed
  6. Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation. 1998, 98: 2227-2234.View ArticlePubMed
  7. Fath-Ordoubadi F, Beatt KJ: Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation. 1997, 96: 1152-1156.View ArticlePubMed
  8. Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H: Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. DIGAMI Study Group. Diabetes Insulin-Glucose in Acute Myocardial Infarction. Eur Heart J. 1996, 17: 1337-1344.View ArticlePubMed
  9. Kannel WB, McGee DL: Diabetes and cardiovascular disease. The Framingham study. Jama. 1979, 241: 2035-2038. 10.1001/jama.241.19.2035.View ArticlePubMed
  10. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A: New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972, 30: 595-602. 10.1016/0002-9149(72)90595-4.View ArticlePubMed
  11. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I:, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989, 2: 358-367.View ArticlePubMed
  12. Madler CF, Paynes N, Wilkenshoff U, Cohen A, Derumeaux GA, Pierard LA, Engvall J, Brodin LA, Sutherland GR, Fraser AG: Non-invasive diagnosis of coronary artery disease by quantitative stress echocardiography: optimal diagnostic models using off-line tissue Doppler in the MYDISE study. Eur Heart J. 2003, 24: 1584-1594. 10.1016/S0195-668X(03)00099-X.View ArticlePubMed
  13. Celutkiene J, Sutherland GR, Laucevicius A, Zakarkaite D, Rudys A, Grabauskiene V: Is post-systolic motion the optimal ultrasound parameter to detect induced ischaemia during dobutamine stress echocardiography?. Eur Heart J. 2004, 25: 932-942. 10.1016/j.ehj.2004.04.005.View ArticlePubMed
  14. Voigt JU, Lindenmeier G, Exner B, Regenfus M, Werner D, Reulbach U, Nixdorff U, Flachskampf FA, Daniel WG: Incidence and characteristics of segmental postsystolic longitudinal shortening in normal acutely ischemic and scarred myocardium. J Am Soc Echocardiogr. 2003, 16: 415-423. 10.1016/S0894-7317(03)00111-1.View ArticlePubMed
  15. Voigt JU, Exner B, Schmiedehausen K, Huchzermeyer C, Reulbach U, Nixdorff U, Platsch G, Kuwert T, Daniel WG, Flachskampf FA: Strain-rate imaging during dobutamine stress echocardiography provides objective evidence of inducible ischemia. Circulation. 2003, 107: 2120-2126. 10.1161/01.CIR.0000065249.69988.AA.View ArticlePubMed
  16. Voigt JU, Nixdorff U, Bogdan R, Exner B, Schmiedehausen K, Platsch G, Kuwert T, Daniel WG, Flachskampf FA: Comparison of deformation imaging and velocity imaging for detecting regional inducible ischaemia during dobutamine stress echocardiography. Eur Heart J. 2004, 25: 1517-1525. 10.1016/j.ehj.2004.05.014.View ArticlePubMed
  17. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS: , et al.Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group developed in conjunction with the European Association of Echocardiography a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005, 18: 1440-1463. 10.1016/j.echo.2005.10.005.View ArticlePubMed
  18. DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979, 237: E214-223.PubMed
  19. Muniyappa R, Lee S, Chen H, Quon MJ: Current approaches for assessing insulin sensitivity and resistance in vivo: advantages limitations and appropriate usage. Am J Physiol Endocrinol Metab. 2008, 294: E15-26. 10.1152/ajpendo.00645.2007.View ArticlePubMed
  20. Borai A, Livingstone C, Ferns GA: The biochemical assessment of insulin resistance. Ann Clin Biochem. 2007, 44: 324-342. 10.1258/000456307780945778.View ArticlePubMed
  21. Turner RC, Holman RR: Pathophysiology of diabetes. Lancet. 1976, 2: 856-10.1016/S0140-6736(76)91247-2.View ArticlePubMed
  22. Chiu WC, Kedem J, Scholz PM, Weiss HR: Regional asynchrony of segmental contraction may explain the "oxygen consumption paradox" in stunned myocardium. Basic Res Cardiol. 1994, 89: 149-162.PubMed
  23. Fan D, Soei LK, Stubenitsky R, Boersma E, Duncker DJ, Verdouw PD, Krams R: Contribution of asynchrony and nonuniformity to mechanical interaction in normal and stunned myocardium. Am J Physiol Heart Circ Physiol. 1997, 273: H2146-2154.
  24. Lucats L, Ghaleh B, Monnet X, Colin P, Bize A, Berdeaux A: Conversion of post-systolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning. Eur Heart J. 2007, 28: 872-879. 10.1093/eurheartj/ehm030.View ArticlePubMed
  25. Przyklenk K, Patel B, Kloner RA: Diastolic abnormalities of postischemic "stunned" myocardium. Am J Cardiol. 1987, 60: 1211-1213. 10.1016/0002-9149(87)90435-8.View ArticlePubMed
  26. Derumeaux G, Ovize M, Loufoua J, Pontier G, Andre-Fouet X, Cribier A: Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue Doppler imaging: characterization of normal ischemic and stunned myocardium. Circulation. 2000, 101: 1390-1395.View ArticlePubMed
  27. Monnet X, Lucats L, Colin P, Derumeaux G, Dubois-Rande J-L, Hittinger L, Ghaleh B, Berdeaux A: Reduction in postsystolic wall thickening during late preconditioning. Am J Physiol Heart Circ Physiol. 2007, 292: H158-164. 10.1152/ajpheart.00406.2006.View ArticlePubMed
  28. Olufadi R, Byrne CD: Clinical and laboratory diagnosis of the metabolic syndrome. J Clin Pathol. 2008, 61: 697-706. 10.1136/jcp.2007.048363.View ArticlePubMed
  29. Bing RJ, Siegel A, Ungar I, Gilbert M: Metabolism of the human heart. II. Studies on fat ketone and amino acid metabolism. Am J Med. 1954, 16: 504-515. 10.1016/0002-9343(54)90365-4.View ArticlePubMed
  30. Wisneski JA, Gertz EW, Neese RA, Mayr M: Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. J Clin Invest. 1987, 79: 359-366. 10.1172/JCI112820.PubMed CentralView ArticlePubMed
  31. Oliver MF, Opie LH: Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet. 1994, 343: 155-158. 10.1016/S0140-6736(94)90939-3.View ArticlePubMed
  32. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG: Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. Cardiovasc Res. 1997, 33: 243-257. 10.1016/S0008-6363(96)00245-3.View ArticlePubMed
  33. Barrett EJ, Schwartz RG, Francis CK, Zaret BL: Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog. J Clin Invest. 1984, 74: 1073-1079. 10.1172/JCI111474.PubMed CentralView ArticlePubMed
  34. Garland PB, Randle PJ: Regulation of glucose uptake by muscles. 10. Effects of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, and of fatty acids, ketone bodies and pyruvate, on the glycerol output and concentrations of free fatty acids, long-chain fatty acyl-coenzyme A, glycerol phosphate and citrate-cycle intermediates in rat heart and diaphragm muscles. Biochem J. 1964, 93: 678-687.PubMed CentralView ArticlePubMed
  35. Newsholme EA, Randle PJ: Regulation of glucose uptake by muscle. 7. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart. Biochem J. 1964, 93: 641-651.PubMed CentralView ArticlePubMed
  36. Stanley WC, Lopaschuk GD, McCormack JG: Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res. 1997, 34: 25-33. 10.1016/S0008-6363(97)00047-3.View ArticlePubMed
  37. Saddik M, Lopaschuk GD: Triacylglycerol turnover in isolated working hearts of acutely diabetic rats. Can J Physiol Pharmacol. 1994, 72: 1110-1119.View ArticlePubMed
  38. Wall SR, Lopaschuk GD: Glucose oxidation rates in fatty acid-perfused isolated working hearts from diabetic rats. Biochim Biophys Acta. 1989, 1006: 97-103.View ArticlePubMed
  39. Rosano GM, Vitale C, Fragasso G: Metabolic therapy for patients with diabetes mellitus and coronary artery disease. Am J Cardiol. 2006, 98: 14J-18J. 10.1016/j.amjcard.2006.07.004.View ArticlePubMed
  40. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ: Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation. 2004, 109: 2191-2196. 10.1161/01.CIR.0000127959.28627.F8.View ArticlePubMed
  41. Abel ED: Myocardial insulin resistance and cardiac complications of diabetes. Curr Drug Targets Immune Endocr Metabol Disord. 2005, 5: 219-226. 10.2174/1568008054064869.View ArticlePubMed
  42. Ahmed SS, Jaferi GA, Narang RM, Regan TJ: Preclinical abnormality of left ventricular function in diabetes mellitus. Am Heart J. 1975, 89: 153-158. 10.1016/0002-8703(75)90039-3.View ArticlePubMed
  43. Zoneraich S, Silverman G, Zoneraich O: Primary myocardial disease, diabetes mellitus, and small vessel disease. Am Heart J. 1980, 100: 754-755. 10.1016/0002-8703(80)90243-4.View ArticlePubMed
  44. Rodrigues B, Cam MC, McNeill JH: Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem. 1998, 180: 53-57. 10.1023/A:1006882805197.View ArticlePubMed
  45. Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, Hintze TH, Lopaschuk GD, Recchia FA: Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation. 2002, 106: 606-612. 10.1161/01.CIR.0000023531.22727.C1.View ArticlePubMed
  46. Hall JL, Lopaschuk GD, Barr A, Bringas J, Pizzurro RD, Stanley WC: Increased cardiac fatty acid uptake with dobutamine infusion in swine is accompanied by a decrease in malonyl CoA levels. Cardiovasc Res. 1996, 32: 879-885.View ArticlePubMed
  47. Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E, Camici PG: Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002, 51: 3020-3024. 10.2337/diabetes.51.10.3020.View ArticlePubMed
  48. Dutka DPIP, Pitt M, Chareonthaitawee P, Di Terlizzi M, Ferranini E:, et al. Type 2 but not type 1 diabetes is associated with myocardial insulin resistance regardless of the presence of coronary artery disease. J Am Coll Cardiol. 2001, 37: 300A.View Article
  49. Knuuti J, Bengel FM: Positron emission tomography and molecular imaging. Heart. 2008, 94: 360-367. 10.1136/hrt.2007.118992.View ArticlePubMed
  50. Kisrieva-Ware Z, Coggan AR, Sharp TL, Dence CS, Gropler RJ, Herrero P: Assessment of myocardial triglyceride oxidation with PET and 11C-palmitate. J Nucl Cardiol. 2009, 16: 411-421. 10.1007/s12350-009-9051-7.PubMed CentralView ArticlePubMed
  51. Gertz EW, Wisneski JA, Stanley WC, Neese RA: Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest. 1988, 82: 2017-2025. 10.1172/JCI113822.PubMed CentralView ArticlePubMed
  52. Monti LD, Landoni C, Setola E, Galluccio E, Lucotti P, Sandoli EP, Origgi A, Lucignani G, Piatti P, Fazio F: Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients. Am J Physiol Heart Circ Physiol. 2004, 287: H1225-1231. 10.1152/ajpheart.00629.2003.View ArticlePubMed

Copyright

© Heck et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement