In order to investigate the effect of euglycemic hyperinsulinemia on skeletal muscle blood flow and renal blood flow, catheters were inserted into both femoral arteries, one femoral vein and one renal vein of 7 healthy men. Constant infusions of indocyanine-green dye (intraarterial) and of p-aminohippuric acid (intra-venous) were used to estimate leg plasma flow (ELPF) and renal blood flow (ERPF), respectively, prior to and during a euglycemic, hyperinsulinemic clamp (1.0 mU/kg.min of human insulin, serum concentrations of insulin before and during the clamp: 4.6 +/- 0.9 microU/ml and 65.5 +/- 20.6 microU/ml, respectively, t = 120 min). ERPF (basal: 1220 +/- 320 ml/min) remained unchanged throughout the period of induced hyperinsulinemia in each volunteer (mean: 1135 +/- 490 ml/min), whereas mean leg plasma flow (ELPF) rose from basal 206 +/- 99 ml/min up to 275 ml/min 90 minutes after the beginning of the euglycemic clamp study (p < 0.01). This was due to the marked rise in ELPF from 149 +/- 24 ml/min up to 243 +/- 25 ml/min (p < 0.01) seen in 5 subjects. In two men, who presented a markedly higher basal ELPF (332 and 365 ml/min, respectively), no further rise in ELPF was seen during induced hyperinsulinemia. Fractional renal extraction of insulin was unchanged during induced hyperinsulinemia (28 +/- 5%; basal: 22 +/- 18%), as was fractional extraction of insulin by the leg (10 +/- 5%; basal: 13 +/- 11%). The observed dissociation of ERPF and ELPF suggests a differential response to insulin in renal vs. leg vasculature which possibly is due to increased peripheral glucose metabolism.

Background Insulin resistance and nonalcoholic fatty liver disease (NAFLD) both relate to cardiovascular mortality. Using a mouse model of chronic lipid overload and secondary-NAFLD-induced insulin resistance (SEC-NAFLD-IR), we recently deciphered that SEC-NAFLD-IR already at young age provoked myocardial lipotoxicity with reduced mitochondrial efficiency and increased vulnerability to cardiac ischemia. However, long-term consequences of SEC-NAFLD-IR remain elusive. Purpose Here we aimed to elucidate the impact of long-term SEC-NAFLD-IR on multiple mitochondrial quality control (mQC) mechanisms in the heart and its consequences for cardiac function. Methods We studied 36 SEC-NAFLD-IR mice (72-week-old). For mechanistic experiments, we applied palmitate-induced insulin resistant murine HL-1 cells. Cardiac mitochondrial dynamics were measured via quantification of mitochondrial morphology and expression of mitochondrial fusion and fission factors (Opa1, Drp1, Fis1, Mfn 1 & 2). Mitophagy level was evaluated via immunofluorescence and protein expression of key mitophagy-related genes (Parkin, NIX, LC3). Mitochondrial biogenesis and mass were examined via quantitation of PGC-1α expression, mtDNA and citrate synthase activity. Results 72-week-old SEC-NAFLD-IR mice exhibited 21% (p=0.001) and 32% (p&lt;0.001) higher body weight and heart weight compared with controls. Along with elevated oxidative stress, hepatic lipid accumulation and inflammation, 6h-fasted SEC-NAFLD-IR mice were characterized by increased plasma glucose, insulin and cholesterol. SEC-NAFLD-IR mice displayed a cardiac phenotype with 21% higher left ventricular mass (normalized to body weight, p&lt;0.001) and 6% lower ejection fraction compared to controls (73.5% SEM 0.90 vs 69.4% SEM 1.65, p=0.04). We found several advantageous mQC mechanisms suppressed in aged SEC-NAFLD-IR mice including long form OPA1-mediated mitochondrial fusion, Parkin- and NIX-mediated mitophagy. Likewise, mitochondrial biogenesis was suppressed in the aged insulin-resistant heart, which was connected to a 65% downregulation of PGC-1α1 expression (p=0.01). Interestingly, downregulation of cardiac PGC-1α1 in aged SEC-NAFLD-IR mice coincided with upregulation of PARIS, indicating the crucial participation of the Parkin/PARIS pathway in mQC of the insulin-resistant heart. In addition, induction of insulin resistance in murine HL-1 cardiomyocytes also led to increased mitochondrial fragmentation and decreased PGC-1α1 expression. Conclusion This study demonstrated that regulation of mitochondrial network and turnover is hampered by SEC-NAFLD-IR in the hearts of aged mice, which may contribute to hypertrophy and cardiac dysfunction in insulin resistance. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Collaborative Research Centre 1116 (German Research Foundation)

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