High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L -lard; HF-O -olive oil; HF-C -coconut fat; HF-F -fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma -3 polyunsaturated fatty acid ( -3-PUFA) and saturated fatty acid (C 12 -C 14 , SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPAR -dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA-or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.

INTRODUCTIONThe course of acute pancreatitis ranges from a mild transitory edematous to a severe necrotizing form. Necrotizing pancreatitis occurs in about 20% of all patients suffering from acute pancreatitis [1] . If infection of the necrotic tissue occurs mortality rates of up to 50% are reported with sepsis and multiorgan failure as most frequent causes [2][3][4][5] . It is generally accepted that in infected necrotizing pancreatitis the infected non-vital solid tissue has to be removed in order to control the sepsis. The standard treatment has traditionally been surgery [5,6] . By using modern surgical techniques like open packing, repeated laparatomies, closed packing or closed continuous lavage mortality rates could be decreased to 20%-40% [7][8][9][10][11][12] . However, these techniques are associated with a considerable surgical trauma which often causes escalation of multiorgan failure and sepsis [7,13] . Moreover, total anaesthesia is mandatory. Thus, in the last decade minimal invasive treatment regimes and in particular percutaneous drainage therapy were included in the management of infected necrotizing pancreatitis. Ultrasound (US) or computed tomography (CT) guided placement of drainages is reported to be effective in up to 90% for drainage of fluid collections or abscesses with purely liquid content [14] . However, the success rates Abstract AIM: To assess the outcome of patients with acute necrotizing pancreatitis treated by percutaneous drainage with special focus on the influence of drainage size and number.

It is possible that activation of protein kinase C (PKC) isoforms by free fatty acids (FFA) plays a role in the failure of pancreatic β-cell mass expansion to compensate for peripheral insulin resistance in the pathogenesis of type-2 diabetes. The effect of lipid moieties on activation of conventional (PKC-α and -β1), novel (PKC-δ) and atypical (PKC-ζ) PKC isoforms was evaluated in an in vitro assay, using biotinylated neurogranin as a substrate. Oleoyl-Coenzyme A (CoA) and palmitoyl-CoA, but not unesterified FFA, significantly increased the activity of all PKC isoforms (P≤0·05), particularly that for PKC-δ. It was found that FFA (0·4 mM oleate/complexed to 0·5% bovine serum albumin) inhibited IGF-I-induced activation of protein kinase B (PKB) in the pancreatic β-cell line (INS-1), but this was alleviated in the presence of the general PKC inhibitor (Gö6850; 1 µM). To further investigate whether conventional or novel PKC isoforms adversely affect β-cell proliferation, the effect of phorbol ester (phorbol 12-myristate 13-acetate; PMA)-mediated activation of these PKC isoforms on glucose/IGF-Iinduced INS-1 cell mitogenesis, and insulin receptor substrate (IRS)-mediated signal transduction was investigated. PMA-mediated activation of PKC (100 nM; 4 h) reduced glucose/IGF-I mediated β-cell mitogenesis (>50%; P≤0·05), which was reversible by the general PKC inhibitor Gö6850 (1 µM), indicating an effect of PKC and not due to a non-specific PMA toxicity. PMA inhibited IGF-I-induced activation of PKB, correlating with inhibition of IGF-I-induced association of IRS-2 with the p85 regulatory subunit of phosphatidylinositol-3 kinase. However, in contrast, PMA activated the mitogen-activated protein kinases, Erk1/2. Titration inhibition analysis using PKC isoform inhibitors indicated that these PMA-induced effects were via novel PKC isoforms. Thus, FFA/PMA-induced activation of novel PKC isoforms can inhibit glucose/IGF-I-mediated β-cell mitogenesis, in part by decreasing PKB activation, despite an upregulation of Erk1/2. Thus, activation of novel PKC isoforms by long-chain acyl-CoA may well contribute to decreasing β-cell mass in the pathogenesis of type-2 diabetes, similar to their inhibition of insulin signal transduction which causes insulin resistance.

Thiazolidinediones (TZDs) have been suggested to act beneficially on pancreatic islet function and on beta-cell viability but data concerning direct effects on isolated islets are controversial. Therefore, we have examined parameters of pancreatic insulin and glucagon secretion and biosynthesis in TZD-exposed rat pancreatic islets under physiological glucose level conditions and under conditions of glucolipotoxicity.Primary rat islets were incubated for 2·5 h with or without troglitazone (10 µM) in 5·6 mM glucose (standard glucose levels) and 16·7 mM glucose (high glucose levels); a subgroup was additionally treated with oleate (200 µM) to simulate acute glucolipotoxicity. Insulin and glucagon secretion, intracellular content and their respective mRNAs were quantified. Newly synthesized insulin was determined by pulse-labeling experiments.Troglitazone reduced insulin secretion at standard and high glucose levels by about one-third (P≤0·05). Insulin content was decreased at 5·6 mM glucose but increased at 16·7 mM glucose by the presence of troglitazone (P≤0·05). Newly synthesized insulin mRNA and preproinsulin mRNA decreased by about 20% at standard glucose levels (P≤0·05). Glucagon secretion was augmented by troglitazone in islets under high glucose conditions by an additional 50% (P≤0·05). No clear beneficial troglitazone effects were observed under glucolipotoxic conditions.The reduced insulin secretion and biosynthesis at standard glucose levels can be interpreted as an insulin-sparing effect. Troglitazone effects were less pronounced at high glucose alone or in combination with oleate. From a clinical point of view, these results indicate a greater benefit of troglitazone for beta-cell function in hyperinsulinemic, but normoglycemic patients with insulin resistance or early type 2 diabetes without major insulin secretion deficits and/or pronounced hyperglycemia.