The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET (microPET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [(18)F]fluorodeoxyglucose ([(18)F]FDG) was reduced by approximately 81% (P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [(18)F]fluorothia-6-heptadecanoic acid ([(18)F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [(11)C]acetate and myocardial perfusion index as assessed by [(13)N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by microPET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was approximately 40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [(18)F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA.

A noninvasive method to determine postprandial fatty acid tissue partition may elucidate the link between excess dietary fat and type 2 diabetes. We hypothesized that the positron-emitting fatty acid analog 14( R, S)-[18F]fluoro-6-thia-heptadecanoic acid (18FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered 18FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant 18FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of 18FTHA in the distal thoracic duct, reaching a peak at time 240 min. 18FTHA mean standard uptake value increased progressively in the liver, heart, quadriceps, and subcutaneous and visceral adipose tissues between time 60 and 240 min. Most circulating 18F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received 18FTHA by gavage, we confirmed that >90% of this tracer reached the circulation as triglycerides. This novel noninvasive method to determine tissue dietary fatty acid distribution in humans should prove useful in the study of the mechanisms leading to lipotoxicity.

Among the second-generation photosensitizers (PS) developed for the treatment of neoplastic diseases by photodynamic therapy (PDT) (Kessel, 1996;Ochsner, 1997), metallo-phthalocyanines (MePc) have been proposed (Spikes, 1986;van Lier, 1990;Rosenthal, 1991) as an alternative to Photofrin (PII), the only PS currently approved for clinical use. Their stronger absorption in the red part of the spectrum (molar extinction coefficient, 2.5 × 10 5 M -1 cm -1 at 675 nm), where the depth of light penetration in tissues is twice that obtained at 630 nm with PII (Svaasand, 1984), together with their chemical homogeneity and their lower potential to induce cutaneous photosensitivity (Roberts et al, 1989;Tralau et al, 1989) are major advantages over PII.Unsubstituted MePc are not soluble in physiological solvents and their in vivo administration relies upon their incorporation into carriers, such as the liposomal formulation of ZnPc (Isele et al, 1995), or their chemical conversion into water-soluble dyes by the attachment of selected substituents onto the benzene rings of the macrocycle. An inverse relationship was related between the degree of substitution by sulphonato groups of MePc and their hydrophobicity and photodynamic activities, both at the cellular level and in tumour-bearing mice (Brasseur et al, 1987(Brasseur et al, , 1988Paquette et al, 1988;Berg et al, 1989;Chan et al, 1990Chan et al, , 1991Margaron et al, 1996a). The potential of the water-soluble aluminium sulphophthalocyanine (AlPcS) to generate activated oxygen species (Sharman et al, 1999) and to induce a photodynamic response in vivo has been widely evaluated, and a mixture of AlPcS bearing 2-4 sulphonato groups per Pc (Photosense) is used extensively and successfully in clinical PDT in Russia (Zharkova et al, 1994). Furthermore, the di-sulphonated derivative has been shown to induce tumour regression mainly via direct tumour cell kill rather than damage to the tumour vasculature, as observed for PII (Chan et al, 1996;Margaron et al, 1996b). The unsubstituted AlClPc has, however, attracted less attention even though it has been shown that this compound formulated as a Cremophor emulsion was preferentially retained by a gliosarcoma and was able to induce tumour necrosis in this model (Dereski et al, 1994). More recently, we demonstrated that the Cremophorformulated AlClPc was more effective in inducing tumour regression in EMT-6 tumour-bearing mice than the mono-through tetrasulphonated derivatives, while exerting relatively minor effects against normal tissues (Chan et al, 1997). The low dosage required together with the absence of systemic toxicity, even at much higher doses, renders the AlClPc Cremophor emulsion one of the most potent photosensitizer preparations currently available in terms of therapeutic window. However, Cremophor oil is known to induce unwanted side-effects in patients (Dye and Watkins, Summary The potential use of unsubstituted aluminium phthalocyanine (AlClPc) as a sensitizer for photodynamic therapy (PDT) of cancer has not been f...

Abstract— The photodynamic properties of the di‐and tetrasulfonated zinc and aluminium phthalocyanines and a tetrasulfonated aluminium napththalocyanine were studied using 2′‐deoxyguanosine as a DNA model compound. The major photooxidation products of this nucleoside were identified and classified according to their formation through a radical mechanism (type I) or a singlet oxygen mediated mechanism (type II). The major type I product was obtained and identified as 2,2‐diamino [(2‐deoxy‐β‐d‐erythropentofuranosyl)‐4‐amino]‐5(2H)‐oxazolone. Two major type II products were characterized as the 4R* and 4S* diastereomers of 9‐(2‐deoxy‐β‐d‐erythropentofuranosyl)‐7,8‐dihydro‐4‐hydroxy‐8‐oxoguanine. In addition a third product, also resulting from a type II photooxidation, was identified as 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine. Quantification of these products provided a means to estimate the contribution of type I and type II pathways during the phthalocyanine and naphthalocyanine mediated photooxidation of 2′‐deoxyguanosine, confirming the major role of singlet oxygen in these processes.