Michael Trautmann - Profile on Academia.edu (original) (raw)

Papers by Michael Trautmann

Biochemical Journal, Mar 15, 1987

The rat insulinoma-derived RINm5F cell line retains many differentiated functions of islet fl-cel... more The rat insulinoma-derived RINm5F cell line retains many differentiated functions of islet fl-cells. However, it fails to recognize glucose as an insulin secretagogue in the physiological concentration range. With this cell line, glucose-transport kinetics were investigated, by using a double-label technique with the non- metabolizable glucose analogue 3-O-methylglucose (OMG). RINm5F cells possess a passive glucosetransport system with high capacity and low affinity. Equilibration across the plasma membrane of extracellular OMG concentrations up to at least 20 mm is achieved within 2 min at 37 'C. The half-saturation of OMG uptake occurs at 32 mm. At lower temperatures OMG uptake is markedly retarded, with a temperature coefficient (Q10) of 2.9. As indicated by effilux measurements, transport is symmetrical. Cytochalasin B at micromolar concentrations and phlorrhizin in millimolar concentrations are potent inhibitors ofOMG uptake. Neutralization of the secreted insulin with antibodies does not alter OMG uptake kinetics. The glucose metabolism of RINm5F cells is much exaggerated compared with that of islet fl-cells. Nonetheless, when measured in parallel to uptake, transport exceeds by far the rate of metabolism at glucose concentrations above 3 mm. Measurements of intracellular D-glucose reveal a lower intracellular glucose concentration relative to the extracellular in RINm5F cells. This seems to be due to abnormalities in the subsequent steps of glucose metabolism, rather than to abnormalities in hexose uptake. The loss of glucose-induced insulin release in RINm5F cells cannot be explained by alterations in hexose transport.

European journal of biochemistry, Jun 1, 1994

To test whether in RINmSF rat insulinoma cells luminal acidity and the activity of a vacuolartype... more To test whether in RINmSF rat insulinoma cells luminal acidity and the activity of a vacuolartype proton pump are involved in calcium sequestration by intracellular calcium stores sensitive to inositol 1,4,5-trisphosphate (InsP,) we examined the effects of various proton-conducting ionophores and ammonium chloride, and of bafilomycin, a specific inhibitor of vacuolar proton pumps, on this parameter. Bafilomycin in concentrations up to 1 pM did not affect calcium sequestration by nonmitochondrial, InsP,-sensitive stores at all; 50 pM carbonylcyanide m-chlorophenylhydrazone, 50 pM monensin and 30 mM NH,Cl, which are diverse ways to dissipate transmembrane pH gradients, did not inhibit calcium sequestration. This argues against significant involvement of internal acidity and vacuolar proton pumps in calcium sequestration by InsP,-sensitive stores in RINmSF cells. The proton-potassium-exchanging ionophore nigericin (20-100 pM), however, inhibited calcium sequestration by nonmitochondrial and InsP,-sensitive stores. This effect was dependent on the presence of potassium and could be reversed by inclusion of carbonylcyanide m-chlorophenylhydrazone or acetate in the incubation medium. Thus, the inhibitory effect of nigericin appears to be based on proton extrusion coupled to potassium influx across the membrane of calcium stores in RINm5F cells, creating an internal alkalinization of these stores. The effect of nigericin implies the continuous maintenance of an outside-to-inside potassium concentration gradient by nonmitochondrial calcium stores in RINmSF cells. This feature will be of potential interest in the identification of InsP,-sensitive calcium-storing organelles.

Annals of Surgery, Nov 1, 1993

The purpose of this study was to determine the value of somatostatin-receptor scintigraphy (SRS) ... more The purpose of this study was to determine the value of somatostatin-receptor scintigraphy (SRS) in the preoperative localization of gastrointestinal endocrine tumors. The authors report their preliminary experiences with this new technique as compared to conventional imaging studies like computed tomography (CT) and ultrasonography (US). Most endocrine tumors possess high-affinity somatostatin-receptors. Using the stable, 111ndium labelled somatostatin analogue pentatreotid, which binds to these receptors, it is possible to detect somatostatin-receptor-positive tumors scintigraphically. In nine patients with various gastrointestinal endocrine tumors, SRS, CT, and US were performed before surgical exploration. The preoperative imaging studies and intraoperative ultrasound (IOUS) were then compared to findings on surgical exploration. Twelve primary tumors were found in 8 patients at surgical exploration. These primary tumors were correctly identified with SRS in five patients, with US in four patients, and with CT in three patients. In one patient with the Zollinger-Ellison syndrome, scintigraphy suggested a tumor in the area of the hepatoduodenal ligament, while CT and US had negative results. The underlying gastrinoma could not be identified despite extensive surgical exploration. Scintigraphy, CT, and US showed comparable results in the detection of metastases in four patients. The data from this small series suggest that SRS is helpful in the preoperative localization of gastrointestinal endocrine tumors.

Investigations into Tissue Distribution and Inhibition of Food Consumption with Efpeglenatide

Diabetes, Jun 22, 2018

Efpeglenatide (efpeg), a long-acting glucagon-like peptide-1 receptor agonist in development for ... more Efpeglenatide (efpeg), a long-acting glucagon-like peptide-1 receptor agonist in development for type 2 diabetes, induces weight loss through satiety and reduced food intake. Studies in Sprague Dawley rats investigated how peripheral and central mechanisms contribute to the anorectic effects of efpeg. Tissue distribution of efpeg was assessed by whole-body autoradioluminography with 14C-efpeg. The contribution of vagal nerve signaling to food intake control was assessed in vagotomized rats treated with exenatide (0.15 or 0.45 nmol/kg twice daily) or efpeg (0.71 or 2.1 nmol/kg every 2 days). Pharmacokinetic parameters and mean radioactivity of 14C-efpeg in selected organs/tissues are shown in Figure. Peak concentration (Cmax) of 14C-efpeg was highest in the kidney cortex; Cmax at all other sites was similar to/lower than in blood, relatively high in the intestine and pituitary, with below-quantifiable levels in the cerebellum/cerebrum. Inhibition of food intake was not attenuated in vagotomized vs. sham-operated rats at higher doses of efpeg (3-day cumulative intake: 47.4 vs. 49.4 g) or exenatide (54.9 vs. 60.7 g), suggesting a non-vagal mechanism for these anorectic effects. These findings suggest that central mechanisms are involved in the anorectic effects of efpeg in this animal model; potential cell-signaling effects of efpeg in the intestine and pituitary need to be investigated further. Disclosure Y. Park: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.

Metabolism-clinical and Experimental, Sep 1, 1992

One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered... more One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 pg Sandostatina three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a "negative" selection of patients included in the trial and suggesting that Sandostatinm cannot prevent disease progress when it is far advanced. In the evaluation of 88 patients monitored for at least 3 months, partial regression was observed in 4.4%. stable disease in 50%. and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatina exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

Inverse Relationship between Glucose Metabolism and Glucose-Induced Insulin Secretion in Rat Insulinoma Cells

Hormone research, 1990

Slowly growing X-ray-induced rat insulinomas and derived cell lines have been used as a model sys... more Slowly growing X-ray-induced rat insulinomas and derived cell lines have been used as a model system for glucose-induced insulin release. During perfusions of tumors transplanted under the kidney capsule, the carbohydrates glucose and D-glyceraldehyde increased insulin secretion. These stimuli and the amino acids leucine and alanine also provoked insulin release in freshly isolated tumor cells. Under these conditions, glucose utilization had a Km of 4.6 mM and maximal velocity of 0.9 nmol/min/10(6) cells. A continuous cell line was established from such a preparation. In culture, glucose-induced insulin secretion was no longer detectable while responses to D-glyceraldehyde and amino acids were retained. Glucose metabolism in the cell line showed a decrease in Km to 0.7 mM glucose and an increased maximal velocity of 1.4 nmol/min/10(6) cells. Attempts to revert these alterations were undertaken using glucose-deficient culture medium to diminish glycolytic flux. Basal insulin release was lowered, while the growth pattern of the cells remained unchanged. Another approach involved the use of sodium butyrate which has been demonstrated to promote differentiation in other cell systems. Whereas sodium butyrate markedly increased cellular insulin content, the secretory responses were not improved. These results provide evidence that the loss of glucose-induced insulin secretion is paralleled by alterations in glucose metabolism.

Diabetes Care, Mar 9, 2010

OBJECTIVE -In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Fact... more OBJECTIVE -In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks. -In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n ϭ 128 QW-only; n ϭ 130 BID3 QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. RESULTS -Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean Ϫ2.0% [95% CI Ϫ2.1 to Ϫ1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C Ͻ7.0% and Յ6.5%, respectively. In both treatment arms, FPG was reduced by Ͼ40 mg/dl, and body weight was reduced by Ͼ4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. CONCLUSION -Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

Diabetes Care, Aug 12, 2019

To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glu... more To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). RESEARCH DESIGN AND METHODS EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallelgroup, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo (n = 37), or liraglutide (£1.8 mg daily; n = 36). The primary efficacy end point was change in HbA 1c from baseline to week 13. RESULTS From a baseline HbA 1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ‡1 mg significantly reduced HbA 1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA 1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ‡1 mg than placebo achieved HbA 1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placeboadjusted LS mean differences 21.4 and 22.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. CONCLUSIONS Efpeglenatide once weekly led to significant reductions in HbA 1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.

BMJ open diabetes research & care, 2022

Introduction Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being develo... more Introduction Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being developed to improve glycemic control in type 2 diabetes (T2D). In the BALANCE 205 study (NCT02075281), efpeglenatide significantly reduced body weight versus placebo in patients with obesity, or overweight with comorbidities, and without T2D. These subanalyses explore the efficacy and safety of efpeglenatide in subgroups of patients with pre-diabetes and stratified by body mass index (BMI) or age from the BALANCE study. Research design and methods The 20-week BALANCE study randomized patients with BMI ≥30 kg/m 2 or ≥27 kg/ m 2 with comorbidities, and without diabetes, to efpeglenatide 4 mg or 6 mg once weekly, 6 mg or 8 mg once every 2 weeks, or placebo. For these subanalyses, patients were stratified by pre-diabetes status (glycated hemoglobin (HbA 1c) 5.7%−6.4% (39-46 mmol/mol) or fasting plasma glucose (FPG) 100-125 mg/dL) and by BMI or age < or ≥ median values (34.9 kg/ m 2 and 44 years, respectively) at baseline. Results In patients with pre-diabetes at baseline, all efpeglenatide doses led to greater proportions of patients reverting to normoglycemia (40.6%-64.3%) versus placebo (10.0%), and greater reductions in HbA 1c (0.30%-0.38%), FPG (7.7-14.1 mg/dL), and weight (5.6-7.3 kg) versus placebo (nominal p<0.05 for all). In patients with BMI or age < or ≥ median, greater reductions in weight were observed with all efpeglenatide doses versus placebo (nominal p<0.01 for all). The most common adverse events in patients receiving efpeglenatide across patient subgroups were gastrointestinal adverse events. Conclusions These results are consistent with the overall BALANCE population and suggest beneficial effects of efpeglenatide on glycemic control and body weight regardless of pre-diabetes status, age, or BMI at baseline. The effects of efpeglenatide on glycemic control in patients with pre-diabetes suggest it might help reduce the likelihood of at-risk patients developing diabetes. http://drc.bmj.com/

BMJ open diabetes research & care, Jun 1, 2021

et al. Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and be... more et al. Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study.

Diabetes Technology & Therapeutics, Nov 1, 2011

Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet... more Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This longacting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(d,l-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, *2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, *7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6-7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly.

Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1

Expert Opinion on Drug Discovery, Dec 12, 2012

The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from t... more The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic β-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss. This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials. GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.

World Journal of Surgery, Jul 1, 1993

Diabetes Care, Mar 23, 2010

OBJECTIVE-To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic ... more OBJECTIVE-To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS-Obese subjects (n ϭ 152; age 46 Ϯ 12 years, female 82%, weight 108.6 Ϯ 23.0 kg, BMI 39.6 Ϯ 7.0 kg/m 2 , IGT or IFG 25%) were randomized to receive exenatide (n ϭ 73) or placebo (n ϭ 79), along with lifestyle intervention, for 24 weeks. RESULTS-Exenatide-treated subjects lost 5.1 Ϯ 0.5 kg from baseline versus 1.6 Ϯ 0.5 kg with placebo (exenatide Ϫ placebo, P Ͻ 0.001). Placebo-subtracted difference in percent weight reduction was Ϫ3.3 Ϯ 0.5% (P Ͻ 0.001). Both groups reduced their daily calorie intake (exenatide, Ϫ449 cal; placebo, Ϫ387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS-Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Somatostatin in der pr�operativen therapie und postoperativen diagnostik eines patienten mit Verner-Morrison-Syndrom

Langenbecks Archiv für Chirurgie, 1992

We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated... more We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated vipoma. Marked tumor-associated hypercalcemia could be treated successfully with somatostatin analogues prior to surgical therapy of the pancreatic tumor. Sixteen months after extirpation of the primary tumor recurrent tumor growth was diagnosed; at this time the patient was clinically asymptomatic and had no abnormal laboratory test results. Liver metastases and local metastases were identified using somatostatin receptor scintigraphy. We report and discuss the use of somatostatin in the treatment of tumor-associated symptoms in endocrine tumors and the possibility of identifying endocrine tumors by means of somatostatin receptor scintigraphy.

Nederlands tijdschrift voor diabetologie, Sep 1, 2013

De behandelingen van eenmaal per week (Dulaglutide) hebben een placebocontrole, terwijl juist de ... more De behandelingen van eenmaal per week (Dulaglutide) hebben een placebocontrole, terwijl juist de relevante vergelijking tussen Dulaglutide en Exenatide open label is met de bijbehorende risico's op een bias. Langetermijnstudies zijn nodig om het consistente eff ect van deze behandelingen op het beloop van de diabetes, de (macrovasculaire) complicaties en de levensverwachting te kunnen beoordelen.

Diabetic medicine : a journal of the British Diabetic Association, Oct 1, 2018

To evaluate the PAQ (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that ... more To evaluate the PAQ (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes. Adults with Type 2 diabetes with HbA concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single-arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA , seven-point self-monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects. A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m , Type 2 diabetes duration 17 ± 8 years, HbA 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selecte...

Standardisiertes chirurgisches Konzept zur Diagnostik und Therapie des Zollinger-Ellison-Syndroms

Deutsche Medizinische Wochenschrift, Mar 25, 2008

ABSTRACT Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years... more ABSTRACT Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years) with Zollinger-Ellison syndrome (ZES) were treated according to a standardized surgical concept. The diagnostic work-up consisted of measuring serum gastrin levels, pre-operative localization by ultrasound and abdominal computed tomography, as well as extensive staging by laparotomy. As complete a tumour resection as possible was the aim of treatment in 15 patients, while in one patient it was to reduce the tumour mass. In six patients who had resection of a solitary tumour there was no evidence of recurrence after 6-42 months of follow-up. Exploration of the duodenum made it possible to identify and then remove a small gastrinoma of the duodenal wall in three patients. No gastrinoma was found in one patient despite extensive exploration. In a further four patients the laparotomy was purely exploratory, because diffuse metastasization was found. In four patients the primary tumour and, where present, the regional lymph nodes were removed, but the signs of ZES persisted, i.e. the intervention was merely palliative. In one female patient, reduction of tumour mass was necessary because the symptoms could not be controlled by conservative measures: she died postoperatively from toxic hepatitis. This experience indicates that standardized surgical intervention achieves potentially curative results in nearly 40% of patients. Including the duodenum in the surgical exploration allows the identification of even small gastrinomas of the duodenal wall. It is concluded that all patients with ZES but no evidence of diffuse metastases should undergo surgical treatment.

Clinical Therapeutics, 2016

Purpose: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved... more Purpose: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective ($ 50 pg/mL) and steady-state ($ 300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses. Methods: This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA 1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed. Findings: Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA 1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA 1c , FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not. Implications: Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.