Cyclosporin A (CyA) was fed to male Wistar rats in a dose of 5, 10 or 50 mg/kg b.wt. for 7 days. In another experimental procedure 10 mg/kg b.wt. CyA was given for 7 days combined with Diltiazem (DIL) 6.25 mg/kg b.wt. once daily ip. Glucose stimulated insulin secretion from the isolated perfused pancreas was investigated in these animals. Total insulin secretion (ng/50 min) was not affected after feeding 5 mg/kg b.wt. CyA, but was significantly decreased with 10 and 50 mg/kg b.wt. CyA. The biphasic insulin secretion was reduced after 5 mg/kg b.wt. CyA during the initial peak (0-10 min) but not during the second peak (10-50 min), whereas after 10 and 50 mg/kg b.wt. CyA both peaks nearly reached base-line levels. DIL markedly increased the initial peak (0-10 min) after feeding CyA 10 mg/kg b.wt., whereas the second peak was not affected. Our results demonstrate a toxic effect of CyA on the pancreatic B-cell, which might be partly abolished by calcium-antagonists.

36 patients (18 males and 18 females, mean age 51 [21-76] years) were prepared for colonoscopy with acupuncture (points: Hegu, Neiguan, Zusanli and Gongsun bilaterally), without acupuncture or pretend acupuncture at points not expected to bring about pain relief. In the 12 acupuncture patients mean pain sensitivity, estimated during the examination by means of a visual analog scale, was significantly (P = 0.003) lower (1.4 +/- 0.4) than in the groups without acupuncture (n = 12; 2.7 +/- 0.3) or pretend acupuncture (n = 12; 3.0 +/- 0.3). In addition, analgesics and sedatives needed to be given significantly less to those with acupuncture (one patient each; P = 0.005) than those without (analgesics to five, sedatives to eight patients) or with pretend acupuncture (analgesics to four, sedatives to five patients). These data demonstrate that pain connected with colonoscopy can be reduced by preceding acupuncture.

Cyclic somatostatin (SRIF) significantly reduces hormonal (Creutzfeldt et al., 1975; Dollinger et al., 1976; Domschke et al., 1976) and non-hormonal (Lankisch et al., 1975) stimulated pancreatic volume and enzyme secretion in man. Linear SRIF inhibits basal and hormonal stimulated enzyme secretion in the rat (Folsch et al., 1976). As 'rest to the gland' is generally considered to be a major aim in the treatment of acute pancreatitis (Trapnell, 1972) the effect of SRIF was investigated in acute experimental pancreatitis in the rat.

Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an "isoglycaemic" intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during "isoglycaemic" intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 +/- 6.9% (100% = response to oral load) in control subjects and 36.0 +/- 8.8% in diabetic patients (p less than or equal to 0.05). The contribution to connecting peptide responses was 58.4 +/- 7.6% in control subjects and 7.6 +/- 14.5% (p less than or equal to 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

In a previous study, mild to moderate exocrine pancreatic insufficiency, as measured by the secretin-pancreozymin test, was found in 23 (43%) of 53 patients with type-1 diabetes mellitus. Of these 53 patients, 20 (7 of whom initially had an abnormal secretin-pancreozymin test) were available for a follow-up examination 11 years later. Of the 7 patients with abnormal exocrine pancreatic function at the first test, 5 remained abnormal and 2 became normal, whereas of the 13 patients with initially normal pancreatic function the test result remained normal in 11 patients and became abnormal in 2. In these 2 groups the test result did not differ significantly between both tests. However, exocrine pancreatic function had returned to normal or had become abnormal in 2 patients, respectively, at the second test. In the 3 patients with exocrine pancreatic insufficiency at the first and second tests, the lipase level had not fallen below 10% or less than the normal level at which steatorrhea occurs and therapy is required. There was no significant correlation between the duration of the diabetes and the test results for both time points of investigation. The data suggest that mild to moderate exocrine pancreatic insufficiency found in type-1 diabetes is due to an early event in the course of the diabetes and does not progress. Therefore, this finding is of minor clinical importance and expensive pancreatic enzyme substitution will not be required.

A follow-up study of first-degree relatives of type 2 diabetic patients presented the opportunity to study the association of components of the metabolic syndrome with oral glucose tolerance in these subjects. In 1992, 25 years after the first analysis of the cohort, we performed 75-g oral glucose tolerance tests and measured anthropometric data (body mass index, waist-hip ratio), insulin and C-peptide concentrations, and parameters of lipoprotein metabolism (free fatty acids, triglycerides, cholesterol, HDL cholesterol). Of 135 participants, 71 had normal glucose tolerance (GT), 22 had impaired GT, and 42 had diabetic GT (WHO 1985 criteria). Impaired glucose tolerance and diabetes were significantly (Kruskal-Wallis test) associated with advanced age (p=0.001), higher body mass index (p=0.005) and waist-hip ratio (p=0.027), systolic hypertension (p=0.031), elevated basal insulin concentrations (p<0.001), higher free fatty acids (p<0.001) and triglycerides (p=0.017), and lower HDL cholesterol (p=0.003); no associations were found with total and LDL cholesterol levels (Friedewald's formula, p=0.25). Abnormalities (obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, pathological oral glucose tolerance) were associated with significant deterioriations in all other components of the metabolic syndrome, if their number exceeded three. Disturbances of oral glucose tolerance are present in a high percentage of first-degree relatives after 25 years of follow-up (51% of those tested). Impaired or diabetic glucose tolerance in such a cohort was associated with overweight, hypertension and disturbances of lipoprotein metabolism characteristic of the metabolic syndrome. Hypercholesterolemia (LDL-cholesterol) is not a component of the metabolic syndrome in a German population with a high hereditary burden regarding type 2 diabetes. A metabolic syndrome should certainly be diagnosed if three components are present, although even in the presence of only two components, an elevated risk is evident.

The scientific achievements of Jens F. Rehfeld, and the impact of the contributions of Jens Rehfeld and his coworkers on our knowledge of gut-brain peptides is reviewed, based on almost 30 years of scientific contact and friendship. The identification of the first gut peptides led to the "immunologic era" and subsequently to the "genetic" era, during which cascades of new knowledge have been generated.

About 25% of common drugs are racemates, i.e. mixtures of their optical or spatial isomers (stereoisomers or enantiomers). Frequently the enantiomers differ in their pharmacokinetics, pharmacodynamics, drug interactions and side effects. Therefore, the pharmaceutical industry, pharmacologists and clinicians are increasingly interested in the development of enantiomers as drugs. Since advances in synthetic and analytical chemistry have provided the tools to produce stereoisomeric drugs, also the authorities recommend and support chiral switch. As example for the therapeutic gain the recent studies with esomeprazole, the first isomeric protonpump inhibitor (iPPI) are summarized and discussed.

Short-term studies with acarbose have demonstrated its efficacy in reducing postprandial blood glucose levels and glycated haemoglobin (HbA(1c)) levels. These effects would be expected to translate into improvements in long-term complications of diabetes, but such data are not yet available due to the long follow-up times required. Animal models of diabetes have, however, demonstrated the efficacy of acarbose in combating the long-term complications of the disease. The 18 animal studies reviewed here showed that acarbose treatment reduced postprandial blood glucose concentrations and decreased protein glycation. Through these actions, acarbose delayed or prevented the onset of renal, retinal, lens and neurological changes and the development of ischaemic myocardial lesions. Acarbose treatment can therefore be expected to benefit patients with Type 2 and, in combination with insulin, Type 1 diabetes. This is being investigated in ongoing clinical studies in patients with Type 2 diabetes and impaired glucose tolerance (IGT).

GLP-1 (7-36 amide) normalizes fasting plasma glucose in NIDDM patients. It was the aim to study the effect of overnight intravenous GLP-1 (7-36 amide) on the following 24 h-glucose profiles. Ten NIDDM patients (7 female, 3 male; age 62 +/- 4 y., BMI (Body-Mass-Index) 29.6 +/- 3.9 kg/m2, duration 10 +/- 7 y., HbA1c 10.9 +/- 1.3% (normal 4.0-6.1%), treated with glibenclamide and/or metformin) were studied on two occasions in random order: Either GLP-1 (7-36 amide) (Saxon Biochemicals, Hannover, FRG, 1 pmol x kg(-1) x min(-1)) or placebo (0.9% NaCl with 1% human serum albumin, Behringwerke, Marburg, FRG) were infused intravenously from 22:00 to 7:00 (9 h) and plasma glucose profiles were obtained during the GLP-1 infusion and the following 24 hours. GLP-1 (7-36 amide) (plasma concentration 110 +/- 12 pmol/l) raised plasma C-peptide concentrations (p = 0.0005), suppressed glucagon (p = 0.01) and lowered plasma glucose to 5.5 +/- 0.6 and 6.3 +/- 0.4 mmol/l at 3:00 and 7:00 a.m. (vs. 10.3 +/- 0.9 and 11.3 +/- 0.6 mmol/l, p = 0.0003 and p < 0.0001, respectively, with placebo). Thereafter, starting 1 h after breakfast, no significant differences in plasma glucose, insulin, C-peptide or glucagon profiles were found between experiments with GLP-1 (7-36 amide) and placebo. Average plasma glucose concentrations over the whole 24 h period were reduced by 18% by GLP-1 administered overnight. In conclusion, (1) overnight GLP-1 (7-36 amide) normalizes fasting plasma glucose, but (2) has no sustained effect on meal-induced glucose, insulin or glucagon concentrations once its administration has been stopped. (3) Normalization of fasting plasma glucose alone does not improve daytime metabolic control in NIDDM patients on oral agents.

To better characterize autonomous insulin secretory behaviour in insulinoma patients and to establish diagnostic criteria with high accuracy, hyperinsulinaemic, sequentially eu‐ and hypoglycaemic clamp tests were performed in insulinoma patients and control subjects. Ten patients with insulinoma (benign in nine, histologically proven in nine) and 10 patients with suspected episodes of hypoglycaemia, in whom thorough clinical evaluation excluded an insulinoma, were examined. Five insulinoma patients were restudied after successful extirpation of the tumour. Suppression of C‐peptide during low‐dose [2 pmol kg –1 min –1 (20 mU kg –1 h –1 ) for 90 min, plasma insulin approximately 120 pmol L –1 (20 mU L –1 )] and high‐dose [8 pmol kg –1 h –1 (80 mU kg –1 h –1 ) for 90 min, plasma insulin approximately 450 pmol L –1 (75 mU L –1 )] insulin infusion under euglycaemic conditions [plasma glucose 4.4–5.0 mmol L –1 (80–90 mg dL –1 )]) and during high‐dose insulin infusion under hypoglycaemic conditions [glucose 2–2.2 mmol L –1 (40–45 mg dL –1 )] was evaluated by radioimmunoassay (RIA). Euglycaemic hyperinsulinaemia suppressed C‐peptide in control subjects ( P < 0.0001), whereas in insulinoma patients apparently irregular changes in C‐peptide concentrations (with spontaneous or paradoxical increments, P = 0.0006 vs. controls) were observed. The combination of hyperinsulinaemia and controlled hypoglycaemia led to a nearly complete suppression of C‐peptide in normal subjects (from basal, 0.76 ± 0.08–0.06 ± 0.01 nmol L –1 ; maximum observed value 0.10 nmol L –1 ), which was more pronounced than at the point of discontinuation of prolonged fasting (> 48 h; 0.26 ± 0.16 nmol L –1 ; P = 0.005). In insulinoma patients, C‐peptide remained elevated under all conditions ( P = 0.51 vs. prolonged fasting). All these findings were reversible after successful surgical removal of the insulinoma. Insulinoma patients could be identified as abnormal by (a) non‐suppression of C‐peptide even under hyperinsulinaemic/hypoglycaemic conditions (10 out of 10 patients) and (b) irregular increments in C‐peptide under conditions that led to at least partial suppression in all normal subjects (9 out of 10 patients) and/or by an apparent shift to the left of insulin secretion relative to glucose concentrations (7 out of 10 patients). Controlled exposure to hyperinsulinaemic/hypoglycaemic conditions can help to characterize autonomous secretion in insulinoma patients and may be used as a diagnostic procedure when conventional methods yield equivocal results.

The course of a first attack of acute pancreatitis was evaluated in a retrospective study of 602 patients, who were admitted between 01.01.1980 and 30.09.1993 to the Centers of Internal Medicine and Surgery of the University of Göttingen (n = 417) and from 16.11.1986 to 30.06.1994 to the Municipal Hospital of Lüneburg (n = 185). Etiology was biliary tract disease in 227 (37.7%), alcohol abuse in 177 (29.4%), unknown in 133 (22.1%), and other causes in 65 (10.8%) patients. Mean hospital stay was 27.9 +/- 24 days (x +/- SD), median 23 days. Pancreatic pseudocysts developed in 14.3% of the patients, and surgical treatment was necessary in 11.1%. Within the first 48 hours, respiratory insufficiency was observed in 63.2% of the 204 patients undergoing arterial blood gas analysis while renal impairment occurred in 32.6% of 602 patients. Artificial ventilation was indicated in 12.5%, and dialysis in 7% of the patients. Mortality rate was 6.1%, correlating significantly with respiratory and renal impairment and procedures in connection with these complications and also with transfers from other hospitals.

The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6 yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume was determined by a dye dilution technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg.min; Saxon Biochemicals) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control experiment, gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concentrations transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, approximately 70 pmol/L), gastric volume remained constant over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree observed, inhibition of gastric emptying, however, must be overcome by tachyphylaxis, reduction in dose, or pharmacological interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.

Division of Medicine Department of Gastroenterology University of Essen Essen, Germany Mayo Medical School Gastroenterology Research Unit Mayo Clinic Rochester, Minnesota, U.S.A.

I. One of the most interesting developments in our knowledge of gastric mucosal pathobiology has been the recognition of the relationship between Helicobacter infection, chronic gastritis, induction of lymphoid follicles in the mucosa (MALT)C and gastric lymphoma. Difficulties in distinguishing histologically between florid reactive lymphoid hyperplasia, sometimes termed "pseudolymphoma," and lymphoid neoplasia have long been recognized. More recently, monoclonality of lymphoid proliferations and the presence of gene rearrangements have been taken as evidence of transformation to a neoplastic state, and molecular techniques have increased our sensitivity over histology in detecting these lesions. However, the demonstration by Isaacson's group, subsequently confirmed by others, that early MALT lymphomas, diagnosed by morphologic and molecular criteria are not autonomous but are driven by specific Helicobacter antigens in the presence ofT cells and regress upon elimination of the Helicobacter infection, is both intriguing and important [1, 2]. First, it has altered our management of patients with early MALT lymphomas of the stomach. Second, it raises as yet unanswered questions about the longterm outcome of these lesions: for example, following regression of the initial tumor, does a population of "tumor" cells remain in the mucosa with the potential for re-emergence if the bacterium is incompletely eradicated or if reinfection occurs, as a few early reports suggest [3]. How can we distinguish reliably between "early" or antigen-dependent lymphoid proliferations and those that are truly autonomous and that, therefore, will not respond to antibiotic therapy? Moreover, it prompts a semantic question concerning the definition of neoplasia: recognizing that its development is a multi-step process, how do we now define when neoplastic transformation has occurred in this setting? Are these early MALT "lymphomas" true neoplasms, or are they merely reactive monoclonal lymphocytic reactions to a persistent foreign antigen, best defined as pre-neoplastic? Finally, it raises fundamental questions as to what molecular changes occur in mucosal B-cells during the progression from reactive gastritis to low-grade and high-grade maltoma and how Helicobacter pylori elicits them. The availability of a mouse model of Helicobacterinduced gastric maltomas offers an opportunity to compare the roles of products generated by Helicobacter and those produced by inflammatory cells in a similar system [4]. In association with studies on readily accessible human gastric biopsy tissue, this may lead to elucidation of the pathogenesis of this interesting lymphoproliferative process.