[Update on type 1 diabetes]. / Update Typ-1-Diabetes.

Type 1a diabetes develops from a chronic autoimmune process leading to absolute insulin deficiency and proneness to ketosis. Prospective studies have clearly shown that intensive insulin therapy (ICT) results in improved quality of life and reduced development of diabetes-associated microvascular and macrovascular complications. The gold standard of therapy in type 1 diabetes is insulin injection with a basal bolus insulin regimen, in which patient daily routine and wishes are considered. The treatment goals should be determined on an individualized basis together with the patient. An HbA(1c) value < 7.0% is considered to be well controlled while values ≤ 6.5% indicate an excellent blood glucose control, as long as there are no episodes of severe hypoglycemia. As many adult patients with type 1 diabetes develop additional cardiovascular risk factors dyslipidemia and hypertension should also be considered and treated according to current treatment guidelines. A multimodal treatment may be the best way to preserve quality of life in patients with type 1 diabetes.

Impact of Octreotide and SOM-230 on liver metastasis and hepatic lipidperoxidation in ductal pancreatic adenocarcinoma in Syrian Hamster.

Octreotide is a somatostatin analogue binding on two receptor subtypes. In previous trials Octreotide showed inhibitory effects on tumour growth and liver metastasis in experimental pancreatic cancer. Thus we evaluated whether the new somatostatin analogue SOM-230 binding on 4 receptor subtypes has superior effects on carcinogenesis in pancreatic carcinoma. About 120 Syrian hamsters were randomised into six groups (n = 20): Gr.1: Aqua/Aqua, Gr.2: BOP/Aqua, Gr.3: Aqua/Octreotide, Gr.4: BOP/Octreotide, Gr.5: Aqua/SOM-230, Gr.6: BOP/SOM-230. Tumour groups 2,4,6 subcutaneously received 10 mg/kg body weight N-nitrosobis-2-oxopropylamin (BOP) weekly for 10 weeks, healthy control Gr.1,3,5 were given aqua. In the 17th week therapy started with Octreotide and SOM-230 for 16 weeks, after 32 weeks animals were sacrificed. Pancreas and liver were histopathologically analysed. Hepatic lipidperoxidation was determined by activities of antioxidative enzymes gluthation-peroxidase (GSH-Px) and superoxiddismutase (SOD) as well as concentration of thiobarbituric-acid reactive substances (TBARS). Incidence of liver metastases was 88.2% in Gr.2 (BOP/Aqua), it was decreased in Gr.4 (BOP/Octreo: 40%) and Gr.6 (BOP/SOM-230: 50%) (P < 0.05). Mean number/animal and mean-2-dimensional size of liver metastases did not differ between tumour groups. Comparing GSH-Px-activity in intrametastatic and extrametastatic hepatic tissue revealed a significant increase extrametastatically in Gr.2 (BOP/Aqua) and Gr.6 (BOP/SOM-230). SOD-activity in liver metastases was decreased in Gr.2 (1,801) (P < 0.05) versus Gr.4 (8,304) and Gr.6 (7,038). Intrametastatic TBARS concentration was increased in Gr.2 compared to Gr.4 (BOP/Octreotid) and Gr.6 (BOP/SOM-230) (P < 0.05). Octreotide and SOM-230 equally reduced liver metastasis in ductal pancreatic adenocarcinoma probably by a reduction of lipidperoxidation.

Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: inhibition of matrix metalloproteinases in pancreatic cancer.

BACKGROUND: Matrix metalloproteinases (MMP) are proteolytic enzymes which degrade the extracellular matrix and therefore play an important role in metastasis. However, the impact of MMP inhibitors (MMPI) on pancreatic cancer is still unclear. Thus we evaluated the influence of selective MMPI Ro 28-2653 on the incidence of liver metastases and the concentration of MMP-2 and MMP-9 in ductal pancreatic adenocarcinoma in Syrian hamster. MATERIAL AND METHODS: One hundred and thirty male Syrian hamsters were randomised into 8 groups (Gr.1-3: n=15, Gr.4-8: n=17). Pancreatic cancer was induced by weekly subcutaneous injection of 10mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight (Gr.4-8) while healthy control Gr. 1-3 received 0.5 ml sodium chloride 0.9%. Gr.1 and 4 had free access to a standard diet, Gr. 2, 3 and 5-8 received a diet rich in polyunsaturated fatty acids, which increases liver metastasis in this model. In week 17 oral therapy started: Gr.3 and 6: 60 mg Eudragit/kg body weight/d (vehicle of MMPI), Gr.7 and 8: 40 mg, respectively, 120 mg RO 28-2653/kg body weight/d; Gr.1, 2, 4, 5: no therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP-2 and MMP-9 were measured in non-metastatic liver and liver metastases. RESULTS: Concentrations of MMP-2 and MMP-9 in liver metastases were decreased by high- and low-dose therapy with MMPI. Furthermore, the incidence of liver metastases was significantly reduced by low-dose therapy with Ro 28-2653. CONCLUSION: Low-dose therapy with Ro 28-2653 decreased liver metastasis due to an inhibition of MMP-2 and MMP-9 concentration in ductal pancreatic cancer.

Impact of polyunsaturated fatty acids on hepato-pancreatic prostaglandin and leukotriene concentration in ductal pancreatic cancer -- is there a correlation to tumour growth and liver metastasis?

Type and composition of polyunsaturated fatty acids (PUFAs) are suspected to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 PUFAs on tumour growth, liver metastasis and concentration of prostaglandins (PG) and leukotrienes (LT) in experimental ductal pancreatic adenocarcinoma. Ninety male hamsters were randomised into six groups (Gr.) (n=15). While Gr. 1-3 were healthy control groups, Gr. 4-6 weekly received subcutaneous injections of 10mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight for 12 weeks in order to induce ductal pancreatic adenocarcinoma. Between week 1 and 16 all animals were fed with a standard diet with a raw fat content of 2.9%. In week 17 Gr. 1-6 were allocated to three types of diets: Gr. 1: standard high fat (=SHF diet, rich in n-6 PUFAs)/Gr. 2: FISH-OIL (rich in n-3 PUFAs)/Gr. 3: SMOF (=mixture of n-3, n-6 and n-9 PUFAs)/Gr. 4: BOP+SHF/Gr. 5: BOP+SMOF/Gr. 6: BOP+FISH-OIL. After 32 weeks all animals were sacrificed and pancreas as well as liver were analysed histologically. Furthermore pancreatic and hepatic concentrations of prostaglandins (PGF1alpha, PGE(2)) and LT were measured. FISH-OIL decreased number of macroscopically visible pancreatic tumours (Gr. 4-6: 54.5% vs. 45.5% vs. 9.1%, P<0.05) as well as incidence of liver metastasis (Gr. 4-6: 90.9% vs. 72.7% vs. 36.4%, P<0.05). Furthermore concentration of PGF(1)(alpha), PGE(2) and LT were significantly increased in pancreatic carcinoma compared to tumour-free tissue. Moreover levels of PGF(1)(alpha) and PGE(2) were higher in liver metastasis than in extrametastatic hepatic tissue. However, in Gr. 6 (FISH-OIL) intrametastatic concentration of LT was significantly lower than in non-metastatic hepatic tissue as well as in Gr. 4 and Gr. 5. FISH-OIL decreased number of visible pancreatic tumours and incidence of histological proven liver metastasis. This effect might be caused by a decrease of intrametastatic concentration of LT compared to extrametastatic hepatic tissue.

Influence of different dietary fat intake on liver metastasis and hepatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters.

OBJECTIVES: Effects of polyunsaturated fatty acids (PUFA) on carcinogenesis are discussed controversially. Thus, tumor growth seems to be influenced by type and composition of fat dietary; however, the pathomechanism is still unknown. Therefore, we investigated the impact of different PUFAs on liver metastasis and hepatic lipid peroxidation in a solid model of ductal pancreatic cancer in Syrian hamsters. METHODS: 90 male hamsters were randomized into 6 groups (n = 15). Accordingly groups 2, 4 and 6 received 10 mg N-nitrosobis-2-oxopropylamine (BOP)/kg body weight weekly by subcutaneous injection for 12 weeks in order to induce ductal pancreatic cancer, while groups 1, 3 and 5 were treated with 0.5 ml 0.9% sodium chloride. All hamsters received a standard fat diet (SFD) rich in n-6 PUFA for 16 weeks (2.9% fat). Afterwards, groups 1 and 2 had free access to SFD, while groups 3 and 4 were given a diet enriched with n-3, n-6 and n-9 PUFA (SMOF) and groups 5 and 6 were fed a diet high in n-3 PUFA (FISH-OIL). After 32 weeks all hamsters were sacrificed in order to determine incidence of pancreatic carcinoma and liver metastasis. Furthermore hepatic activities of glutathionperoxidase (GSH-Px) and superoxiddismutase (SOD) as well as levels of lipidperoxidation were analyzed intra- and extrametastatically. RESULTS: The incidence of liver metastasis was decreased in the FISH-OIL tumor group compared to the SFD and SMOF groups. However, GSH-Px activity was not influenced by different diets. Extrametastatic hepatic SOD activity did not differ between all groups, while intrametastatic hepatic SOD activity in the SFD-BOP group was increased. In the FISH-OIL-BOP and the SMOF-BOP group intrametastatic SOD activity was lower than in non-metastatic hepatic tissue. Furthermore levels of hepatic lipid peroxidation were decreased in the tumor groups treated with fish oil and SMOF compared to the SFD group. Comparing intra- and extrametastatic TBARS concentration there was no difference in the SFD-BOP and the SMOF-BOP groups, while in the FISH-OIL-BOP group intrametastatic TBARS concentration was increased. CONCLUSION: Conclusively, fish oil reduced the incidence of liver metastasis in experimental ductal pancreatic cancer. Maybe this effect is caused by an increase of intrametastatic hepatic lipid peroxidation.

Does enteral nutrition of dietary polyunsaturated fatty acids promote oxidative stress and tumour growth in ductal pancreatic cancer? Experimental trial in Syrian Hamster.

BACKGROUND: Type and composition of dietary fat intake is supposed to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 polyunsaturated fatty acids (PUFA) on oxidative stress (lipidperoxidation) and tumour growth in ductal pancreatic cancer. METHODS: Ninety male hamsters were randomized into 6 groups (gr.) (n=15) and allocated to 3 main dietary categories: gr. 1 and 2 received a standard high fat diet (SHF, rich in n-6 PUFA), while gr. 3 and 4 were fed with a diet containing a mixture of n-3, n-6 and n-9 PUFA (SMOF) and gr. 5 and 6 had free access to a diet rich in n-3 PUFA (FISH-OIL). Gr. 1, 3 and 5 received weekly subcutaneous (s.c.) injections of 10 mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight in order to induce ductal pancreatic adenocarcinoma. Healthy control gr. 2, 4 and 6 were treated with 0.5 ml 0.9% sodium chloride s.c. After 32 weeks all animals were sacrificed. Removed pancreata were weighed and analysed histologically and biochemically. Activities of glutathionperoxidase (GSH-Px), superoxiddismutase (SOD) and levels of lipidperoxidation were measured in samples of pancreatic carcinoma as well as in tumour-free pancreatic tissue. RESULTS: While different diets did not significantly alter the overall incidence of histologically proven pancreatic adenocarcinoma, the number of macroscopically visible tumours was decreased in the FISH-OIL-gr. CONCLUSION: Different diets did not significantly influence the incidence of histologically proven pancreatic adenocarcinoma. However, administration of a diet rich in n-3 PUFA (FISH-OIL) resulted in a decrease of macroscopically visible tumours, thus indicating its beneficial effects in respect to attenuation of tumour growth.

n-3, n-6, and n-9 polyunsaturated fatty acids--which composition in parenteral nutrition decreases severity of acute hemorrhagic necrotizing pancreatitis in rats?

BACKGROUND AND AIMS: Acute pancreatitis often requires parenteral nutrition. Thus, we analyzed, using a randomized trial, whether different fatty acids in parenteral nutrition influence lipidperoxidation and histopathology in acute pancreatitis in rats. MATERIALS AND METHODS: Seventy-five male Sprague-Dawley rats were randomized into five groups (gr.) (n=15). Gr. 1 underwent a laparotomy followed by saline infusion, gr. 2-5 received intraductal glycodeoxycholic acid (GDOC) followed by intravenous cerulein. Six hours after induction of pancreatitis (IOP), gr. 2 received saline infusion, while gr. 3 was infused with standard lipovenous (rich in [n-6] polyunsaturated fatty acids (PUFA)), gr. 4 received ClinOleic (rich in [n-9] PUFA), while gr. 5 was infused with Omegaven (rich in [n-3] PUFA) for 18 h. After 24 h, all animals were sacrificed and the pancreas was determined histopathologically according to the severity of pancreatitis. Furthermore, pancreatic lipidperoxidation (TBARS) and activity of lipid production protective enzymes superoxide dismutase (SOD) and gluthationperoxidase (GSHPx) were analyzed. RESULTS: Omegaven infusion reduced the severity of histopathologic changes in acute pancreatitis and decreased lipidperoxidation (TBARS) in pancreatic tissue samples. Furthermore, pancreatic activity of SOD was increased. However, standard PUFA and ClinOleic infusion did not influence the severity of pancreatitis and lipidperoxidation. CONCLUSION: Parenteral nutrition high in n-3 PUFA seems to be superior to compositions of n-6 or n-9 PUFA in the treatment of acute hemorrhagic pancreatitis in rats.

Effects of selective COX-2 and 5-LOX inhibition on prostaglandin and leukotriene synthesis in ductal pancreatic cancer in Syrian hamster.

Selective inhibition of eicosanoid synthesis seems to decrease carcinogenesis, however, the effect on liver metastasis in pancreatic cancer is still unknown. Ductal pancreatic adenocarcinoma was chemically induced by weekly injection of N-nitrosobis-2-oxopropylamine (BOP) in Syrian hamster. Animals received selective inhibition of cyclooxygenase-2 (Celebrex) and 5-lipoxygenase (Zyflo). In week 33, hamsters were sacrificed and incidence of pancreatic carcinomas as well as liver metastases were examined. Furthermore, size and number of liver metastases per animal were determined and concentration of PGF1alpha, PGE2 and leukotrienes was measured in hepatic and pancreatic tissue. Combined therapy (Celebrex+Zyflo) significantly decreased incidence, number and size of liver metastases. Furthermore extra- and intrametastatic concentration of PGE2 was reduced by this treatment in hepatic tissue. Single Cox-2-inhibition (Celebrex) decreased intrametastatic hepatic PGF1alpha and PGE2 concentration while PGF1alpha concentration was reduced in non-metastatic liver (nml). Moreover 5-LOX-inhibition (Zyflo) decreased intrametastatic PGE2 concentration as well as PGF1alpha and PGE2 in nml. In pancreatic carcinomas highest LT-concentration was found after combined treatment and this therapy group was the only one revealing a significantly higher amount of LTs in carcinomas compared to tumour-free tissue. Hepatic LT-concentration was significantly lower in the control groups than in nml of the tumour groups. Combination of Cox-2-inhibition and 5-Lox-inhibition might be a suitable adjuvant therapy to prevent liver metastasis in human ductal pancreatic adenocarcinoma.

Effects of the antioxidative vitamins A, C and E on liver metastasis and intrametastatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters.

BACKGROUND/AIMS: Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (alpha-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster. METHODS: One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1-4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5-8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given alpha-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue. RESULTS: Retinol and alpha-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins. CONCLUSION: Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Sonographic findings in hepatic involvement of hereditary haemorrhagic telangiectasia.

AIM: Hereditary haemorrhagic telangiectasia, or Rendu-Osler-Weber disease, is an autosomal-dominant disorder characterised by angiodysplastic lesions (telangiectases and arteriovenous malformations) which affect many organs including the skin, lungs, gastrointestinal tract, and brain. A broad spectrum of vascular and structural changes have been reported. Our objective was to systematically examine the prevalence of sonographic findings in hepatic involvement in patients with hereditary haemorrhagic telangiectasia (HHT). METHODS: We studied 22 consecutive patients with hereditary haemorrhagic telangiectasia by ultrasonography in combination with colour-Doppler and pulsed wave-Doppler for liver involvement. The clinical diagnosis of HHT was based on the Curaçon criteria. RESULTS: Sixteen of the 22 patients had signs of hepatic involvement including prominent common hepatic artery (14 of 16), dilatation of the intrahepatic part of the hepatic arteries (15 of 16) and intrahepatic AV-shunts (16 of 16). Ectasia of the hepatic vein, fibrotic parenchymal changes, left accessory hepatic artery and focal hepatic lesions were found less frequently. CONCLUSION: Diagnosis of liver involvement in HHT can be made by sonography with colour-Doppler. The main features of this involvement include prominent common hepatic artery, dilatation of the intrahepatic part of the hepatic arteries and intrahepatic AV-shunts.

[Hypophyseal ACTH-cell carcinoma after several surgical interventions and radiotherapy]. / Hypophysäres ACTH-Zellkarzinom nach mehreren chirurgischen Eingriffen und Strahlentherapie.

HISTORY AND ADMISSION FINDINGS: A 56-year-old woman was admitted to our hospital with headache, especially on the left temporal side, dizziness and exercise intolerance. She had been operated three times and radiotherapy once because of pituitary adenoma with intermittend hypercortisolism. The clinical examination was without abnormal findings apart from left temporal pain on pressure on the top of the skull. INVESTIGATIONS: Blood tests were entirely normal. At cranial magnet resonance imaging (cMRI) a left temporal tumor of 10 mm diameter was diagnosed. TREATMENT AND COURSE: The first histological study of the excized lesion could not clarify the diagnosis completely. Because of a local recurrent tumor of 20 mm, a second operation was necessary two months later. Due to structural and immunohistological similarities this tumor was identified as a metastasis of a pituitary ACTH-cell carcinoma. The patient was given adjuvant stereotactic radiotherapy. Two years after the treatment, no tumor recurrence was seen by cMRI. CONCLUSION: Carcinomas of the pituitary are very rare. They can be diagnosed only by their metastases. The pathogenesis is still unclear. It is debatable, whether surgery and/or X-ray therapy in the past may influence tumor development.