Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c).

BACKGROUND: Diabetes mellitus secondary to pancreatic diseases is a condition seldom thought of in clinical practice. Yet, a high percentage of exocrine pancreatic insufficiency has been reported for the general population and especially for diabetic subjects. Thus, we investigated the prevalence of diabetes mellitus due to pancreatic diseases. METHODS: In this study, we investigated 1868 patients diagnosed with diabetes mellitus who had been admitted to our hospital during the last 24 months. Patient data were diligently studied, and patients were reclassified according to the diabetes classification as proposed by the American Diabetes Association. RESULTS: Among 1868 subjects, 172 patients could be classified as type 3c diabetes mellitus (9.2%). Among these were 135 diagnosed with chronic pancreatitis (78.5%), 12 with hereditary haemochromatosis, 14 with pancreatic cancer and 7 with cystic fibrosis. Thus, diabetes mellitus due to chronic pancreatitis occurred in this collective in 7.2% of all diabetic subjects. Misclassification of these patients was very common. Only 51.2% (88/172) were initially classified correctly. Most type 3 diabetes patients were initially misclassified as type 2 diabetes (69/84). CONCLUSIONS: Diabetes mellitus secondary to pancreatic diseases (especially chronic pancreatitis) seems more common than generally believed with a prevalence of 9.2% among the subjects studied here. Because the awareness of this diabetes type is poor, misclassification is quite frequent. A common problem seems to be the differentiation between type 2 and type 3. Yet, the right classification of diabetes mellitus is important, because there are special therapeutic options and problems in patients with diabetes secondary to pancreatic diseases.

Determinants of Exocrine Pancreatic Function as Measured by Fecal Elastase-1 Concentrations (FEC) in Patients with Diabetes mellitus.

OBJECTIVE: Recently it has been shown that there is not only endocrine insufficiency in diabetic patients, but a frequent co-morbidity of both, the endocrine and exocrine pancreas. The present study was performed to further analyse the determinants of exocrine pancreatic function in patients with diabetes mellitus. METHODS: The records of 1992 patients with diabetes mellitus who had been treated in our hospital during a 2-year period were re-evaluated. Defined parameters were documented in standardized data sheets. Records were further checked for the results of imaging procedures of the pancreas. In 307 patients FEC had been performed and documented. Only these patients were included in further evaluation. RESULTS: FEC was inversely correlated with diabetes duration and HbA1c-levels but not with age. C-peptide levels correlated positively with FEC. BMI and FEC were also significantly correlated. There was no correlation between diabetes therapy and exocrine pancreatic function as there was no correlation with any concomitant medication. The presence of diabetes-associated antibodies was not related to FEC. According to the documented data 38 were classified as type-1 diabetes (12.4%), 167 as type-2 (54.4%), and 88 patients met the diagnostic criteria of type-3 (28.7%). Fourteen patients could not be classified because of lacking information (4.6%). CONCLUSIONS: Exocrine insufficiency might be explained as a complication of diabetes mellitus. However, it is more likely that type-3 diabetes is much more frequent than previously believed. Consequently the evaluation of exocrine function and morphology should be included into the clinical workup of any diabetic patient at least at the time of manifestation.

Influence of cholesterol and fat in food on indirect parameters of exocrine pancreatic function.

Fecal elastase 1, chymotrypsin activity, and fat content in stool are clinical parameters of exocrine pancreatic function. The aim of this study was to clarify the possible impact of extreme changes in diet on fecal enzyme concentration/activity, since extreme diets may lead to wrong conclusions in the diagnosis of pancreatic insufficiency. Twelve healthy test persons followed 4 diet phases, each with a duration of 6 days. The 4 diet phases were (1) nearly fat-free with a low-cholesterol content; (2) high in fat and low in cholesterol; (3) high in cholesterol deriving from meat, and (4) high in cholesterol deriving from eggs. At the end of each diet phase, a 72-hour stool collection was carried out to measure fecal elastase 1, chymotrypsin and fecal fat content. The results showed no significant changes after each of the 4 diet phases. The clinical parameters of fecal elastase 1 and chymotrypsin activity in stool do not seem to be significantly influenced by fat and cholesterol deriving from food.

[Pyruvate kinase M2 (tumor M2-PK) as a screening tool for colorectal cancer (CRC). A review of current published data]. / Pyruvatkinase M2 (Tumor M2-PK) im Stuhl als Screeningparameter für kolorektale Neoplasien. Eine Ubersicht über bisher publizierte Daten.

INTRODUCTION: Colonoscopy is currently supposed to be the best screening tool for colorectal cancer. However, the acceptance of the population is very poor although it has been included in screening programs in the German health system since 2002. Therefore, evaluation of additional screening tools seems to be of great interest. Recently testing for fecal occult blood (FOBT), genetic alterations or alterations in tumor metabolism (e.g., tumor M2-PK) are under investigation. METHODS: The use of M2-PK measurement in the feces has been reported in 6 studies until today. The data of these studies were analyzed and critically reviewed. RESULTS: The overall sensitivity of M2-PK is 77.9% concerning CRC. Specificity ranges from 74.3-83.3%. Overall sensitivity for adenomas is 45.9%, increasing to 61.1% for adenomas > 1 cm. A high percentage of positive results (90.4%) was also observed in patients with chronic inflammatory bowel disease. CONCLUSIONS: Compared to FOBT or genetic testing the M2-PK test seems to be superior for CRC screening. Concerning handling, effectiveness and analysis, M2-PK seems to be a good possibility for large scale-screening of colorectal carcinoma. It might even be used to detect larger adenomas. Elevated levels of M2-PK in patients with acute and/or chronic inflammatory bowel diseases are probably due to proliferation of epithelial cells and leucocytes in the inflammatory area.

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer.

Proliferating cells, especially tumour cells, express a special isoenzyme of pyruvate kinase, termed M2-PK, which can occur in a tetrameric form with a high affinity to its substrate, phosphoenolpyruvate (PEP), and in a dimeric form with a low PEP affinity. In tumour cells, the dimeric form is usually predominant and is therefore termed Tumour M2-PK. The levels of Tumour M2-PK within tumours and in EDTA-plasma correlate with staging and the ability of the tumour cells to metastasise. Since most colorectal tumours grow intraluminally, it appeared interesting to determine whether Tumour M2-PK is detectable in the faeces of tumour patients. Stool samples were tested by ELISA from controls without colorectal cancer and colorectal cancer patients. Whereas Tumour M2-PK levels were low in the control group (mean value+/-s.e.m.: 3.3+/-0.4, n=144), they were high in the case of colorectal cancer (56.1+/-15.3, n=60). At a cutoff value of 4 U ml(-1), the sensitivity was 73%. TNM and Dukes' classification of the tumours revealed a strong correlation between faecal Tumour M2-PK levels and staging. The determination of Tumour M2-PK in faeces provides a new promising screening tool for colorectal tumours.

The commercially available ELISA for pancreatic elastase 1 based on polyclonal antibodies does measure an as yet unknown antigen different from purified elastase 1. Binding studies and clinical use in patients with exocrine pancreatic insufficiency.

The measurement of fecal elastase 1 concentrations by means of an ELISA based on monoclonal antibodies (mABs) highly specific for human elastase 1 (ELISA 1) has become an accepted indirect test of the exocrine pancreatic function during the last years. Its use has been demonstrated in many clinical studies including comparison with direct function tests and ERCP morphology. Recently, a new ELISA, also named "elastase 1" based on polyclonal antibodies (pABs; ELISA 2) became available. In the present investigation we performed binding studies with purified elastase 1 as well as studies on patients with exocrine insufficiency with both ELISAs. Surprisingly, the pABs on the solid phase (catcher antibodies) of ELISA 2 did not bind purified elastase 1. These antibodies seem to react with an as yet unknown antigen associated with elastase 1. Measurement of samples from patients suspected to suffer from exocrine insufficiency showed a weak correlation of both assays but higher levels in ELISA 2, resulting in false normal results even in some patients with pancreatic steatorrhea. Since the reference range used in both assays has been established using ELISA 1, ELISA 2 must be re-evaluated in comparison to direct function tests. ELISA 2 should be renamed, since obviously it does react with an antigen (antigens) different from elastase 1.

Measurement of fecal pyruvate kinase type M2 (tumor M2-PK) concentrations in patients with gastric cancer, colorectal cancer, colorectal adenomas and controls.

BACKGROUND: The determination of Tumor M2 Pyruvate Kinase (Tumor M2-PK) in EDTA plasma has been described as a tumor marker in a variety of different tumor types. Since most GI tumors grow intraluminally, it appeared interesting to determine whether Tumor M2-PK is detectable in the feces of tumor patients. MATERIALS AND METHODS: Measurements were performed with a commercially available ELISA (ScheBo Biotech AG, Giessen, Germany) modified for fecal analysis. Samples of controls, GI cancer and adenoma patients were tested. RESULTS: Fecal Tumor M2-PK concentrations could be quantified. A significant difference between cancer patients and controls was found. The highest concentrations were observed in colorectal cancer. However, fecal Tumor M2-PK was not detectable in 5 tumor patients. CONCLUSION: The measurement of fecal Tumor M2-PK concentrations might provide an interesting screening tool for colorectal cancer. Further studies comparing the determination of Tumor M2-PK in stool to occult blood in stool are in progress.

Fecal pyruvate kinase concentrations (ELISA based on a combination of clone 1 and clone 3 antibodies) for gastric cancer screening.

BACKGROUND: Recently we were able to demonstrate that Tumor M2 Pyruvate Kinase (Tumor M2-PK) is detectable in the feces of patients with gastrointestinal (GI) cancer. In this study an ELISA based on a different combination of antibodies was used to investigate stool samples of GI cancer patients. PATIENTS AND METHODS: The ELISA (ScheBoBiotech AG, Giessen, Germany) was based on one antibody specific for Tumor M2-PK and a second antibody reacting with Tumor M2-PK, M1-PK and the tetrameric M2-PK. Stool samples of healthy controls, patients with inflammatory bowel disease (IBD) and different kinds of GI cancer were tested. RESULTS: Compared to controls, samples of IBD or different tumors did not show significant differences, except those patients with gastric cancer (elevated fecal PK in 80% (p = 0.005)). CONCLUSION: If the present results can be confirmed in larger patient samples, this new test might provide an excellent screening tool for gastric cancer.

Enhancement of beta-cell sensitivity to glucose by oral fat load.

Recent studies have demonstrated that 6 h infusions of lipid emulsion enhance insulin release, whereas 24 h infusions inhibit insulin secretion. How insulin release is modulated after oral fat loading has not yet been elucidated. 17 healthy fasting volunteers were subjected to 3 experiments in random order: test 1 was a frequently sampled i. v. glucose tolerance test (FSIVGTT, 0.3 g/kg glucose), test 2 began with the ingestion of 50 % sunflower oil (1.5 g/kg) followed by FSIVGTT 4 h later. Test 3 was identical to test 2 with i. v. addition of 100 U/kg heparin prior to FSIVGTT. Glucose and insulin data were analyzed by minimal model assumptions - glucose sensitivity of the beta-cells (Theta1), acute insulin response (AIR) (10 min), 3 h insulin release (Theta2), glucose threshold of insulin secretion (h), insulin degradation rate (n), peripheral insulin sensitivity (S(I)), and glucose-dependent glucose disposal (S(G)). After drinking the fat emulsion, FFAs increased to 0.8 +/- 0.3 mmol/l (test 2) and to 3.0 +/- 0.3 mmol/l (test 3). Moderately increased FFA concentrations were associated with elevation of Theta1 (test 1, control 335 +/- 157 vs. test 2: 859 +/- 612 pM x min x mM(-1), p = 0.030). At high plasma FFA levels and in the presence of heparin (test 3), Theta1 was reduced compared to test 2 and unchanged compared to test 1. Theta2 and h were elevated in both tests 2 and 3 compared to test 1. No changes of n, S(I) and S(G) were found. In conclusion, the ingestion of sunflower oil triglyceride emulsion resulted in a 60 % increase in plasma free fatty acids and enhanced the capacity of beta-cells to secrete insulin. Heparin-induced high levels of FFA further augmented the total insulin release and inhibited parameters of glucose responsiveness.

Tumor M2-pyruvate kinase: a promising tumor marker in the diagnosis of gastro-intestinal cancer.

The diagnostic value of pyruvate-kinase type tumor M2 (Tumor M2-PK) has been investigated in different tumors, and showed interesting results in cases of renal cancer, pancreatic cancer, lung cancer and some cases of gastric cancer. In this study we investigated EDTA-plasma of 68 patients with gastrointestinal cancer, 22 patients with inflammatory bowel disease (IBD) and 60 healthy controls. Sensitivity of Tumor M2-PK was 70.6% for all GI-tumors, that of CA19-9 was 55.4% and that of CEA was 53.3%. In pancreatic cancer CA19-9 showed the best sensitivity. In oesophageal/gastric cancer Tumor M2-PK was most sensitive and in colorectal cancer CEA and Tumor M2-PK showed the best results. The specificity of Tumor M2-PK was 90-96, 7%. In IBD some individuals showed elevated Tumor M2-PK levels but there was no correlation to CRP or to the clinical activity score. The results indicated that Tumor M2-PK might be a valuable marker in gastrointestinal cancer.

Evaluation of serum levels of solubilized adhesion molecules and cytokine receptors in coronary heart disease.

OBJECTIVES: The diagnostic importance of circulating solubilized tumor necrosis factor-alpha receptor II (sTNF-alphaRII) and interleukin-2 receptor in coronary heart disease (CHD) was evaluated. In addition, these variables were correlated with solubilized adhesion molecule levels (i.e., intracellular adhesion molecule [ICAM], vascular cell adhesion molecule [VCAM], and E-selectin). BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory process. Because the immunologic network presents an abundance of positive and negative feedback mechanisms, information obtained from different immunologic variables might be highly redundant. METHODS: In a cross-sectional study design, 60 patients with angiographically proven CHD were compared with 60 individuals who had undergone coronary angiography but in whom no evidence of stenosis could be found (control subjects). Angiography was performed at least one year before the study. Cytokine levels were determined by enzyme-linked immunosorbent assay technique and evaluated by univariate and multivariate statistical methods. RESULTS: All immunologic variables except E-selectin (p = 0.08) significantly discriminated between patients and control subjects. Coronary artery bypass graft surgery after angiography did not lead to significant differences in the variables investigated in the patients with bypass surgery as compared with the subjects without bypass surgery. Receiver-operating characteristics analysis showed comparable test accuracy for solubilized adhesion molecules and cytokine receptors. Multivariate logistic regression analysis, including age, revealed that only ICAM and sTNF-alphaRII were independently correlated with the presence of CHD. Patients belonging to the third tertile of at least one of these two variables demonstrated a 1.6- to 2-fold increased relative risk for the presence of CHD. CONCLUSIONS: We concluded that both circulating ICAM and TNF-alphaRII should be further evaluated as markers for atherosclerotic changes in the coronary system.

Prevalence of risk factors of coronary heart disease in Turks living in Germany: The Giessen Study.

Turkish people represent the majority of immigrants in Germany. Even though a high proportion of Turks has been living in Germany since about 20 years, little is known about risk factors of coronary heart disease (CHD) in this population. In this study a sample of 325 male and 155 female Turks are investigated, who voluntarily underwent a health check-up in Germany. Data about the presence of CHD, risk factors and blood parameters were collected. Mean residence time was 21 and 17 years (males/females). A low percentage of female participants was observed compared to the general Turkish population in Germany. Age adjusted prevalence of CHD reached 9.5% in males and 6.7% in females, respectively. Dyslipoproteinemia (DLP) showed the highest prevalence of all risk factors investigated in both genders. Total cholesterol (TC) levels were comparable to those of other western countries and remarkably higher than reported for the population in Turkey. Besides this, low high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) levels could be found in the majority of the sample. The highest odds ratios for CHD were estimated for stress and hypertension in males and obesity in females. It is concluded that Turkish immigrants in Germany showed an assimilation of lipid pattern to western populations. However, reasons for low HDL-C levels remain unclear. Changes in the lipid metabolism chiefly seem to contribute to the risk factor pattern of Turkish immigrants in Germany.

Diagnostic relevance of interleukin pattern, acute-phase proteins, and procalcitonin in early phase of post-ERCP pancreatitis.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis has been suggested as a model for acute pancreatitis (AP), which allows evaluation of early alterations in the time course of the disease. The influence of the clinical course on procalcitonin (PCT), serum amyloid A (SAA), and several proinflammatory and inhibitory cytokines was evaluated in patients with AP following ERCP. Blood samples were prospectively collected from patients undergoing ERCP. The incidence of ERCP-induced pancreatic damage, defined as abdominal complaints, a threefold increase of serum lipase, and elevation of CRP from <10 to >20 mg/liter was 12.8% (12/94). Only mild clinical courses of acute pancreatitis were observed. PCT significantly increased in subjects with post-ERCP pancreatitis after 24 hr. However, PCT levels did not exceed 0.5 ng/ml in any patient. Interleukin-1 receptor antagonist (IL-1RA) began to differ from baseline 2 hr after ERCP, followed by interleukin-6 (IL-6, 6 hr), solubilized tumor necrosis factor-alpha receptor II (sTNF-alphaRII, 24 hr) and SAA (24 hr). Interleukin 10 (IL-10) showed marked interindividual variations with no obvious peak. Among all parameters evaluated, only peak values of IL-6 and IL-10 showed significant correlations with the reported pain score (r2 = 0.62/0.78), degree of ampullar irritation (r2 = NS/0.87), and the duration of ERCP (r2 = 0.58/0.76). No correlation was found with the volume of the injected contrast agent. We conclude that IL-10 and IL-6 appear to be useful to monitor patients after ERCP. The absence of any PCT elevation in the present study is in accordance with the clinical course of the patients who suffered from mild pancreatic damage without systemic or infectious complications.

Polymorphisms of apolipoproteins A-IV and E in a Turkish population living in Germany.

Human apolipoproteins (apo) E and apo A-IV are polymorphic with significantly different allele frequencies among different ethnic groups. Whereas the variation at the apo E gene locus affects plasma cholesterol levels in all populations studied so far and is associated with longevity in Caucasians, the influence of the common apo A-IV polymorphism on plasma lipoproteins has not been unanimously accepted. We have therefore determined the common apo E and apo A-IV polymorphisms by isoelectric focusing, calculated the respective allele frequencies and studied their effects on plasma lipoproteins in a random sample of 240 nonrelated Turkish subjects (141 males, 99 females) living in Germany and originating from central and eastern Anatolia. When compared with the German population and other Caucasians in Europe a prominence of the apo epsilon 3 allele frequency (0.885) was accompanied by a decrease in the frequencies of both the apo epsilon 2 allele (0.048) and the apo epsilon 4 allele (0.067). Thus, the Turkish population studied here clustered with populations mainly from southern Europe and Japan, which have low epsilon 2 and epsilon 4 allele frequencies. Also, the frequency of the A-IV-1 allele was higher (0.967) and that of the A-IV-2 allele lower (0.033) in the Turkish subjects studied than in other populations. At an average level of total cholesterol of 194.5 +/- 45 mg/dl, no significant influence of the A-IV alleles on plasma lipoproteins was seen. However, apo E and apo B differed significantly between apo E phenotypes, with high levels of apo E and low levels of cholesterol and apo B in carriers of the epsilon 2 allele, and vice versa for the epsilon 4 allele. The average cholesterol excess for the epsilon 2 allele was -7.95 mg/dl, for the epsilon 3 allele, -1.34, and for the epsilon 4 allele, + 14.15 mg/dl. Thus, despite the unusual frequency distribution of the apo E alleles, their effects on plasma lipoproteins are within the range reported for other populations in Europe.

Fish oil-enriched diet and reduction of low-dose streptozocin-induced hyperglycemia. Inhibition of macrophage activation.

Repeated low doses of streptozocin (STZ; 40 mg/kg, 5 injections/day) induce hyperglycemia in certain strains of mice after a latency of 1 wk. Omega-3 polyunsaturated fatty acids (omega 3FA) have been reported to suppress immune processes by blockade of the cyclooxygenase pathway of arachidonic acid metabolism. We investigated the effects of diets high in omega 3FA on the development of diabetes in the low-dose STZ-induced diabetes (LDSTZ-D) model. Male C57BL/6J mice were on a fish oil diet (FOD) as a source of omega 3FA 8 wk before STZ injection. Controls received laboratory chow only or a coconut oil diet (COD). Blood glucose levels in FOD mice were reduced (12.5 vs. 28 mM for COD mice, P less than .001) 60 days after STZ injection with a diet in which 20% of the calories were from fish oil. In FOD mice, immunohistology showed reduced numbers of class II antigen-expressing cells in pancreatic islets followed by a decreased extent of insulitis. FOD significantly decreased the number of Fc receptor-negative dendritic cells in cytospin preparations of islets isolated from diabetic mice. Interleukin 1-like activity of peritoneal exudate cell supernatants isolated from mice on FOD was reduced. FOD did not improve insulin secretion of isolated islets from LDSTZ-D mice. These data indicate a beneficial effect of FOD on the immune component of the mouse LDSTZ-D model.

CI-924 effects on plasma lipids in patients with type II and type IV hyperlipoproteinaemia.

CI-924 (CI), 5,5'-[[1,1'-biphenyl]-2,5-diylbis(oxy)]bis[2,2- dimethylpentanoic acid] is chemically similar to gemfibrozil. Patients with Type II (n = 13) and Type IV (n = 22) hyperlipoproteinaemia (HLP) were maintained 12 weeks on a baseline diet containing 55% sugar, 15% protein 30% fat and less than 300 mg cholesterol daily to stabilize weight and lipids. They were then entered in a parallel group double-blinded protocol and received 0, 300, 600, or 1200 mg CI p.o. daily for 12 weeks. CI consistently elevated anti-atherogenic HDL and lowered VLDL at 600 mg/day in both Type II and Type IV HPL at 8 weeks. In Type II patients, CI lowered cholesterol, decreased LDL/HDL and increased ApoA-I. In Type IV patients, CI also lowered TC while elevating LDL and ApoA-II. CI had no effect on Apo-B, LDL-ApoB, or Apo-E.

Structure and biochemical effects of fenofibrate.

The structures of various fibric acid derivatives are compared. Fenofibrate inhibits de novo hepatic fatty acid synthesis and seems to inhibit hepatic very low-density lipoprotein synthesis, but it enhances mitochondrial and peroxisomal fatty acid oxidation and lipoprotein lipase activity. It produces a very significant reduction in the plasma triglyceride concentration. Fenofibrate also inhibits cholesterol synthesis prior to processing mevalonate, indirectly causing significant reduction of hydroxymethylglutaryl coenzyme A reductase activity. The drug may inhibit acyl-coenzyme A-cholesterol transferase activity, reducing cholesterol ester accumulation within cells. Fenofibrate significantly increases the fractional rate of lecithin-cholesterol acyltransferase activity in normolipidemic and hypercholesterolemic patients. This may explain the increase in cholesterol ester levels observed in high-density lipoproteins. It may stimulate bile acid synthesis from exogenous cholesterol. It causes a marked reduction of increased spontaneous platelet aggregation. Fenofibrate also markedly diminishes the effect of platelet-derived growth factor upon DNA synthesis in vitro, an effect that might impede a key event in early atherogenesis. Thus, fenofibrate has effects not directly related to its lipid- and lipoprotein-lowering action.