PANCREAS ALERTS
Curr Biol 2003;13:105-15. (AN 22434985, PMID 12546783)
Experimental conversion of liver to pancreas.
Horb ME, Shen CN, Tosh D, Slack JM.
Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath. Bath, United Kingdom
The liver and the pancreas arise from adjacent regions of endoderm in embryonic development. Pdx1 is a key transcription factor that is essential for the development of the pancreas and is not expressed in the liver.
The aim of this study was to determine whether a gene overexpression protocol based on Pdx1 would be able to cause conversion of liver to pancreas.
The authors show that a modified form of Pdx1, carrying the VP16 transcriptional activation domain, can cause conversion of liver to pancreas, both in vivo and in vitro. Transgenic Xenopus tadpoles carrying the construct TTR-Xlhbox8-VP16:Elas-GFP were prepared. Xlhbox8 is the Xenopus homolog of Pdx1, the TTR (transthyretin) promoter directs expression to the liver, and the GFP is under the control of an elastase promoter and provides a real-time visible marker of pancreatic differentiation.
In the transgenic tadpoles, part or all of the liver is converted to pancreas, containing both exocrine and endocrine cells, while liver differentiation products are lost from the regions converted to pancreas.
The authors concluded that the conversion of liver to pancreas could be the basis of a new type of therapy for insulin-dependent diabetes. Although expression of the transgene is transient, once the ectopic pancreas is established, it persists thereafter.
The timing of events is such that the liver is differentiating by the time Xlhbox8-VP16 is expressed, so we consider this a transdifferentiation event rather than a reprogramming of embryonic development. Furthermore, this same construct will bring about transdifferentiation of human hepatocytes in culture, with formation of both exocrine and endocrine cells.
Gastroenterology 2003; 124(7):1830-45. (AN 22689112, PMID 12806617)
Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells.
Liao Q, Guo J, Kleeff J, Zimmermann A, Buchler MW, Korc M, Friess H.
Department of General Surgery, University of Heidelberg. Heidelberg, Germany.
In both pancreatic cancer and chronic pancreatitis, there is enhanced expression of mitogenic growth factors and their tyrosine kinase receptors, which have the capacity to activate mitogen-activated protein kinase (MAPK).
In view of the important role of MAPK kinase phosphatase (MKP)-1 in the regulation of MAPK activation, the expression and functional role of MKP-1 was analyzed.
Pancreatic tissues were analyzed by Northern blotting, Western blotting, and immunohistochemistry. Pancreatic cancer cells were transfected with a full-length MKP-1 antisense construct. Growth characteristics and tumorigenicity in vivo and the effects of mitogenic growth factors on cell growth and MAPK activation were determined in transfected and control cells.
MKP-1 messenger RNA (mRNA) levels were increased in pancreatic cancer and chronic pancreatitis (CP) tissues. Moderate to strong MKP-1 immunoreactivity was present in the cancer cells, ductal cells of pancreatic intraepithelial neoplasia, and in tubular complexes in CP. Down-regulation of MKP-1 resulted in decreased anchorage-dependent and -independent growth of pancreatic cancer cells, and decreased tumorigenicity in a nude mouse tumor model. MKP-1 down-regulation led to decreased proliferation and sustained MAPK activation in response to mitogens.
The authors concluded that suppression of MKP-1 expression reduces the tumorigenicity of pancreatic cancer cells in vivo, suggesting that MKP-1 contributes to enhanced mitogenic signaling in pancreatic cancer cells.
Endoscopy 2003; 35(7):553-8. (PMID 12822088)
A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis.
Dite P, Ruzicka M, Zboril V, Novotny II.
Department of Medicine and Gastroenterology. Brno, Czech Republic.
Invasive treatment for abdominal pain due to chronic pancreatitis may be either surgical or endoscopic, particularly in cases of ductal obstruction. To date, the data published on the effectiveness of these two forms of therapy have been mostly retrospective, and there have been no randomized studies.
A prospective, randomized study comparing surgery with endoscopy in patients with painful obstructive chronic pancreatitis was therefore conducted.
Consecutive patients with pancreatic duct obstruction and pain were invited to participate in a randomized trial comparing endotherapy and surgery, the latter consisting of resection and drainage procedures, depending on the patient's individual situation.
In the entire group, the initial success rates were similar for both groups, but at the 5-year follow-up, complete absence of pain was more frequent after surgery (37% vs. 14%), with the rate of partial relief being similar (49% vs. 51%).
The authors concluded that surgery is superior to endotherapy for long-term pain reduction in patients with painful obstructive chronic pancreatitis. Better selection of patients for endotherapy may be helpful in order to maximize results. Due to its low degree of invasiveness, however, endotherapy can be offered as a first-line treatment, with surgery being performed in case of failure and/or recurrence.
Patients who did not agree to participation and randomization were also further assessed using the same follow-up protocol.
Of 140 eligible patients, only 72 agreed to be randomized.
Surgery consisted of resection (80%) and drainage (20%) procedures, while endotherapy included sphincterotomy and stenting (52%) and/or stone removal (23%).
In the randomized subgroup, results were similar (pain absence: 34% after surgery vs. 15% after endotherapy; relief: 52% after surgery vs. 46% after endotherapy).
The increase in body weight was also greater in the surgical group, while new-onset diabetes developed with similar frequency in both groups, again with no differences between the results for the whole group and the randomized subgroup.
Am J Gastroenterol 2003; 98(6):1305-8. (AN 22702259, PMID 12818274)
Risk of acute pancreatitis in users of azathioprine: a population-based case-control study.
Floyd A, Pedersen L, Lauge Nielsen G, Thorlacius-Ussing O, Toft Sorensen H.
Department of Clinical Epidemiology at Aalborg and Aarhus University Hospitals. Aalborg, Denmark.
Azathioprine has been linked to subsequent acute pancreatitis in several case reports and small case series.
The authors examined the risk for acute pancreatitis in users of azathioprine in North Jutland County, Denmark, with about 490,000 inhabitants.
Patients with incident cases of acute pancreatitis from the Hospital Discharge Registry of the county from 1991-2000 were identified, and selected 10 controls per case, matched by age and sex, from the Central Personal Registry using incidence density sampling technique.
A total of 1,388 patients and 13,836 controls were included in the study. The authors found that 1,317 persons in the entire population redeemed a total of 15,811 prescriptions of azathioprine in the county.
The results of this study show that there was a substantially increased relative risk of acute pancreatitis in users of azathioprine.
All prescriptions of azathioprine within 90 days before admission were likewise collected from the population-based North Jutland Prescription Database. Data on potential confounders were extracted from registries. Conditional logistic regression was used to adjust for confounding.
The incidence rate for acute pancreatitis among all users of azathioprine was one per 659 treatment year. The crude OR of having redeemed prescriptions for azathioprine within 90 days before admission for acute pancreatitis was 7.5 (95% CI = 2.6-21.6). After adjustment for gallstone disease, alcohol-related diseases, inflammatory bowel disease, and use of glucocorticoids, the OR increased to 8.4 (95% CI = 2.4-29.4).
The population-attributable risk, which measures the proportion of all cases of pancreatitis that are attributable to the use of azathioprine in the study population, was 0.4%.
Hepatogastroenterology 2003; 50(51):861-6. (AN 22712389, PMID 12828105)
RES function and liver microcirculation in the early stage of acute experimental pancreatitis.
Forgacs B, Eibl G, Wudel E, Franke J, Faulhaber J, Kahrau S, Buhr HJ, Foitzik T.
Department of Surgery II, Semmelweis Medical University. Budapest, Hungary.
The reticuloendothelial system and in particular, the Kupffer cells in the liver, are important for eliminating antigens and toxic substances in many diseases including acute pancreatitis. Optimal Kupffer cell function is believed to depend on numerous factors including intact hepatic blood supply and microcirculation.
The aim of the study was to evaluate whether hepatic microcirculation and Kupffer cell function are impaired in acute pancreatitis and whether enhancement of hepatic capillary blood flow leads to improved reticuloendothelial system function.
Acute pancreatitis was induced in rats by intraductal infusion of bile salt followed by i.v. cerulein hyperstimulation. Animals were randomized to receive either a selective endothelin-A receptor antagonist (ET-RA; LU-135252; 50 mg/kg) or saline.
Six hours after acute pancreatitis induction, hepatic capillary blood flow and nanocoll clearance were significantly decreased in saline-treated animals (compared to saline-treated healthy controls).
The authors concluded that reticuloendothelial system function and hepatic capillary blood flow are impaired (only) in the early stage of this acute pancreatitis model.
Sham-operated animals (intraductal and i.v. saline infusion) treated according to the same protocol served as controls.
Liver phagocytic function was evaluated in 6 animals per group 6 and 24 hrs after acute pancreatitis induction and treatment using 99mTc-labeled nanocoll and a scintillation camera technique.
Another 6 animals of each group were used for intravital microscopic determination of hepatic capillary blood flow using fluorescein-labeled erythrocytes.
Endothelin-A receptor antagonist significantly improved hepatic capillary blood flow and nanocoll clearance. This beneficial effect was no longer seen after 24 hrs when these parameters had spontaneously returned to values not significantly different from normal.
Endothelin-A receptor antagonist improves hepatic capillary blood flow at this stage.
Enhancement of hepatic capillary blood flow is accompanied by normalization of nanocoll clearance, suggesting that hepatic microcirculation influences phagocytic Kupffer cell function early in acute pancreatitis.
Pancreas 2003; 27(1):E1-5. (AN 22711393, PMID 12826911)
Acute pancreatitis in HIV-infected patients: are etiologies changing since the introduction of protease inhibitor therapy?
Bush ZM, Kosmiski LA.
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Health Sciences Center. Denver, Colorado.
Hypertriglyceridemia is a well-established cause of acute pancreatitis in the general population. Protease inhibitor (PI) therapy, introduced in 1996 for HIV infection, is associated with moderate to severe hypertriglyceridemia.
Aim of the study was to determine whether the prevalence of hyperlipidemic pancreatitis in HIV-infected patients has increased since the introduction of PIs.
This was a retrospective study of patients with acute pancreatitis and HIV infection admitted to three local hospitals between 1990 and 2001.
Before PIs became available (1990-1995), 30 index cases of acute pancreatitis in the setting of HIV infection were identified, and one of these cases (3.3%) was attributed to hypertriglyceridemia.
Despite the well-established association between PIs and hypertriglyceridemia, there was no significant increase in the prevalence of hyperlipidemic pancreatitis in this HIV-infected population after the introduction of PIs. Medication-associated pancreatitis remains the most common cause of acute pancreatitis in the era of potent antiretroviral therapy.
After the introduction of PIs (1996-2001), 54 cases of acute pancreatitis in HIV-infected patients were identified, and two of these cases were attributed to hypertriglyceridemia (3.7%; P=0.6).
In both time periods, medication-induced pancreatitis was the most common cause of pancreatitis in HIV-infected patients.
Am J Kidney Dis 2003; 42(1):53-61. (AN 22712456, PMID 12830456)
Inflammatory parameters are independently associated with urinary albumin in type 2 diabetes mellitus.
Navarro JF, Mora C, Maca M, Garca J.
Nephrology Service and Research Unit, Universitary Hospital Nuestra Seņora de Candelaria. Santa Cruz de Tenerife, Spain.
Data about the relationship of inflammation to nephropathy in type 2 diabetes mellitus are scarce.
In the present study, the hypothesis that inflammatory parameters are independently related to urinary albumin excretion (UAE) at early stages of nephropathy was tested.
Sixty-five patients with type 2 diabetes with microalbuminuria (MAB) or mild proteinuria (protein <1 g/dL) were included. Serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-alpha), as well as urinary level of this cytokine were analyzed.
Inflammatory parameters were significantly greater in patients with diabetes than controls; furthermore, urinary TNF-alpha levels increased significantly as nephropathy progressed.
In conclusion, inflammatory parameters in patients with type 2 diabetes at an early stage of nephropathy are independently associated with UAE. In addition to traditional metabolic and hemodynamic factors, it is possible to hypothesize on the participation of inflammation in the pathogenesis of diabetic nephropathy.
Median urinary TNF-alpha level was 7 pg/mg in normoalbuminurics, 13 pg/mg in microalbuminurics (P<0.001), and 18 pg/mg in proteinurics (P<0.001 versus normoalbuminuria and P <0.01 versus MAB).
Albuminuria was related to hs-CRP (r=0.68; P<0.001) and serum (r=0.45; P<0.01) and urinary TNF-alpha levels (r=0.71; P<0.001), but there was no association between serum and urinary TNF-alpha levels.
Partial correlation analysis showed that hs-CRP level, urinary TNF-alpha level, duration of diabetes, and glycated hemoglobin level remained significantly associated with UAE.
A stepwise multiple regression analysis showed that UAE was significantly associated with hs-CRP level (P<0.001), duration of diabetes (P<0.001), urinary TNF-alpha level (P<0.01), and glycated hemoglobin level (P<0.05; adjusted r2=0.73; P<0.001).
Diabetologia 2003: Jun 27. (PMID 12830381)
Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects.
Wenyi Z, Suzuki S, Hirai M, Hinokio Y, Tanizawa Y, Matsutani A, Satoh J, Oka Y.
Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine. Sendai, Japan.
Urotensin II is a potent vasoactive hormone and the urotensin II gene (UTS2) is localized to 1p36-p32, one of the regions reported to show possible linkage with Type 2 diabetes in Japanese subjects.
The aim of this study is to investigate a possible contribution of SNPs in the UTS2 gene to the development of Type 2 diabetes. METHODS.
We surveyed SNPs in the UTS2 gene in 152 Japanese subjects with Type 2 diabetes mellitus and two control Japanese cohorts: one consisting of 122 elderly subjects who met stringent criteria for being non-diabetic, including being older than 60 years of age with no evidence of diabetes (HbA1c)<5.6%), and another 268 subjects with normal glucose tolerance.
The authors identified two SNPs with amino acid substitutions, designated T21M and S89N. The allele frequency of 89N was higher in Type 2 diabetic patients than in both elderly normal subjects (P=0.0018) and subjects with normal glucose tolerance (p=0.0011), whereas the allele frequency of T21M was essentially identical in these three groups.
These results suggest that the S89N polymorphism in the UTS2 gene is associated with the development of Type 2 diabetes, via insulin sensitivity, in Japanese subjects.
Furthermore, in the subjects with normal glucose tolerance, 89N was associated with higher insulin concentrations on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N.