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

BackgroundCongenic 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.PurposeTo 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.MethodsCardiac 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.ResultsCompared 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).ConclusionsObese 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 AcknowledgementType of funding sources: Public grant(s) – EU funding. Main funding source(s): IMI-SUMMI

Cereal yield gaps across Europe

Europe accounts for around 20% of the global cereal production and is a net exporter of ca. 15% of that production. Increasing global demand for cereals justifies questions as to where and by how much Europe’s production can be increased to meet future global market demands, and how much additional nitrogen (N) crops would require. The latter is important as environmental concern and legislation are equally important as production aims in Europe. Here, we used a country-by-country, bottom-up approach to establish statistical estimates of actual grain yield, and compare these to modelled estimates of potential yields for either irrigated or rainfed conditions. In this way, we identified the yield gaps and the opportunities for increased cereal production for wheat, barley and maize, which represent 90% of the cereals grown in Europe. The combined mean annual yield gap of wheat, barley, maize was 239 Mt, or 42% of the yield potential. The national yield gaps ranged between 10 and 70%, with small gaps in many north-western European countries, and large gaps in eastern and south-western Europe. Yield gaps for rainfed and irrigated maize were consistently lower than those of wheat and barley. If the yield gaps of maize, wheat and barley would be reduced from 42% to 20% of potential yields, this would increase annual cereal production by 128 Mt (39%). Potential for higher cereal production exists predominantly in Eastern Europe, and half of Europe’s potential increase is located in Ukraine, Romania and Poland. Unlocking the identified potential for production growth requires a substantial increase of the crop N uptake of 4.8 Mt. Across Europe, the average N uptake gaps, to achieve 80% of the yield potential, were 87, 77 and 43 kg N ha−1 for wheat, barley and maize, respectively. Emphasis on increasing the N use efficiency is necessary to minimize the need for additional N inputs. Whether yield gap reduction is desirable and feasible is a matter of balancing Europe’s role in global food security, farm economic objectives and environmental targets