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Impact of metabolic substrate modification on myocardial efficiency in a rat model of obesity and diabetes

Virta, J ; Silvola, J.M.U. ; Kiugel, M ; Liljenback, H ; Berglund, Lisa LU ; Garcia Vaz, Eliana LU orcid ; Dutius Andersson, Anna-Maria LU ; Zetterqvist, Anna LU orcid ; Oikonen, V and Jauhianen, M , et al. (2022) In European Heart Journal, Supplement 43(2). p.3076-3076
Abstract
Background

Congenic leptin receptor deficient rat generated by introgression of the Koletsky leptin receptor mutation into BioBreeding Diabetes Resistant rat (BBDR.lepr−/−) is a novel animal model combining obesity, systemic insulin resistance and diabetes. Systemic insulin resistance is associated with reduced myocardial glucose utilization, but its effect on myocardial external efficiency, i.e. the ability of the myocardium to convert energy into external stroke work, remains uncertain.
Purpose

To characterize cardiac energy metabolism and function in BBDR.lepr−/− rats and to study the effect of dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin in this model.
Methods

Cardiac phenotype was evaluated... (More)
Background

Congenic leptin receptor deficient rat generated by introgression of the Koletsky leptin receptor mutation into BioBreeding Diabetes Resistant rat (BBDR.lepr−/−) is a novel animal model combining obesity, systemic insulin resistance and diabetes. Systemic insulin resistance is associated with reduced myocardial glucose utilization, but its effect on myocardial external efficiency, i.e. the ability of the myocardium to convert energy into external stroke work, remains uncertain.
Purpose

To characterize cardiac energy metabolism and function in BBDR.lepr−/− rats and to study the effect of dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin in this model.
Methods

Cardiac phenotype was evaluated in six-month-old male BBDR.lepr−/− rats (n=11) and age-matched male non-diabetic lean control littermates (BBDR.lepr+/− or BBDR.lepr+/+ rats, n=14). Of these, 7 BBDR.lepr−/− rats and 6 controls underwent cardiac ultrasound, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), and [11C]acetate PET in order to evaluate cardiac structure and function as well as glucose and oxidative metabolism. In the remaining rats, fatty acid metabolism was evaluated by [18F]fluorothia-6-heptadecanoic acid ([18F]FTHA) PET/CT. In the linagliptin intervention study, 25 BBDR.lepr−/− male rats were randomly divided into control group (n=11) that received regular chow diet and linagliptin group (n=14) that received linagliptin (10mg/kg/d) mixed in the chow diet for three months. After the intervention, the rats underwent cardiac ultrasound, [18F]FDG PET/CT, and [11C]acetate PET.
Results

Compared with controls, BBDR.lepr−/− rats showed increased left ventricle (LV) mass (∼40%, p>0.001) and higher systolic blood pressure (∼10%, p=0.02). However, fractional shortening and cardiac output were similar in both groups. Myocardial fractional uptake rate of glucose measured with [18F]FDG PET was significantly reduced (∼86%, p=0.004) (Fig. 1A, E), whereas myocardial fatty acid uptake measured by [18F]FTHA PET was not significantly increased (free fatty acid (FFA) corrected standardized uptake value (SUV) ∼21%, p=0.54) (Fig. 1B) in BBDR.lepr−/− compared to controls. Myocardial oxygen consumption assessed by [11C]acetate PET was similar in both groups (Fig. 1C, E), but LV work per gram of myocardium was reduced (∼28%, p=0.001) resulting in reduced myocardial external efficiency (∼21%, p=0.03) (Fig. 1D) in BBDR.lepr−/− compared to controls. Treatment with linagliptin significantly enhanced myocardial fractional uptake rate of glucose (∼166%, p=0.006) (Fig. 2A, C), but had no effect on efficiency of cardiac work (Fig. 2B).
Conclusions

Obese and diabetic BBDR.lepr−/− rats demonstrate LV hypertrophy and markedly reduced myocardial glucose utilization associated with impaired myocardial external efficiency despite normal LV systolic function. Enhancement of myocardial glucose uptake by linagliptin did not improve efficiency of cardiac work.
Funding Acknowledgement

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): IMI-SUMMIT (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Heart Journal, Supplement
volume
43
issue
2
pages
1 pages
publisher
Oxford University Press
ISSN
1520-765X
DOI
10.1093/eurheartj/ehac544.3076
language
English
LU publication?
yes
id
54524b0b-4783-41e0-83b9-ed28ac95cbc2
date added to LUP
2023-09-01 15:16:08
date last changed
2023-09-04 09:52:14
@misc{54524b0b-4783-41e0-83b9-ed28ac95cbc2,
  abstract     = {{Background<br/><br/>Congenic leptin receptor deficient rat generated by introgression of the Koletsky leptin receptor mutation into BioBreeding Diabetes Resistant rat (BBDR.lepr−/−) is a novel animal model combining obesity, systemic insulin resistance and diabetes. Systemic insulin resistance is associated with reduced myocardial glucose utilization, but its effect on myocardial external efficiency, i.e. the ability of the myocardium to convert energy into external stroke work, remains uncertain.<br/>Purpose<br/><br/>To characterize cardiac energy metabolism and function in BBDR.lepr−/− rats and to study the effect of dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin in this model.<br/>Methods<br/><br/>Cardiac phenotype was evaluated in six-month-old male BBDR.lepr−/− rats (n=11) and age-matched male non-diabetic lean control littermates (BBDR.lepr+/− or BBDR.lepr+/+ rats, n=14). Of these, 7 BBDR.lepr−/− rats and 6 controls underwent cardiac ultrasound, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), and [11C]acetate PET in order to evaluate cardiac structure and function as well as glucose and oxidative metabolism. In the remaining rats, fatty acid metabolism was evaluated by [18F]fluorothia-6-heptadecanoic acid ([18F]FTHA) PET/CT. In the linagliptin intervention study, 25 BBDR.lepr−/− male rats were randomly divided into control group (n=11) that received regular chow diet and linagliptin group (n=14) that received linagliptin (10mg/kg/d) mixed in the chow diet for three months. After the intervention, the rats underwent cardiac ultrasound, [18F]FDG PET/CT, and [11C]acetate PET.<br/>Results<br/><br/>Compared with controls, BBDR.lepr−/− rats showed increased left ventricle (LV) mass (∼40%, p&gt;0.001) and higher systolic blood pressure (∼10%, p=0.02). However, fractional shortening and cardiac output were similar in both groups. Myocardial fractional uptake rate of glucose measured with [18F]FDG PET was significantly reduced (∼86%, p=0.004) (Fig. 1A, E), whereas myocardial fatty acid uptake measured by [18F]FTHA PET was not significantly increased (free fatty acid (FFA) corrected standardized uptake value (SUV) ∼21%, p=0.54) (Fig. 1B) in BBDR.lepr−/− compared to controls. Myocardial oxygen consumption assessed by [11C]acetate PET was similar in both groups (Fig. 1C, E), but LV work per gram of myocardium was reduced (∼28%, p=0.001) resulting in reduced myocardial external efficiency (∼21%, p=0.03) (Fig. 1D) in BBDR.lepr−/− compared to controls. Treatment with linagliptin significantly enhanced myocardial fractional uptake rate of glucose (∼166%, p=0.006) (Fig. 2A, C), but had no effect on efficiency of cardiac work (Fig. 2B).<br/>Conclusions<br/><br/>Obese and diabetic BBDR.lepr−/− rats demonstrate LV hypertrophy and markedly reduced myocardial glucose utilization associated with impaired myocardial external efficiency despite normal LV systolic function. Enhancement of myocardial glucose uptake by linagliptin did not improve efficiency of cardiac work.<br/>Funding Acknowledgement<br/><br/>Type of funding sources: Public grant(s) – EU funding. Main funding source(s): IMI-SUMMIT}},
  author       = {{Virta, J and Silvola, J.M.U. and Kiugel, M and Liljenback, H and Berglund, Lisa and Garcia Vaz, Eliana and Dutius Andersson, Anna-Maria and Zetterqvist, Anna and Oikonen, V and Jauhianen, M and Knuuti, J and Nuutila, P and Roivainen, A and Gomez, Maria F and Saraste, A}},
  issn         = {{1520-765X}},
  language     = {{eng}},
  month        = {{10}},
  note         = {{Conference Abstract}},
  number       = {{2}},
  pages        = {{3076--3076}},
  publisher    = {{Oxford University Press}},
  series       = {{European Heart Journal, Supplement}},
  title        = {{Impact of metabolic substrate modification on myocardial efficiency in a rat model of obesity and diabetes}},
  url          = {{http://dx.doi.org/10.1093/eurheartj/ehac544.3076}},
  doi          = {{10.1093/eurheartj/ehac544.3076}},
  volume       = {{43}},
  year         = {{2022}},
}