Empagliflozin Normalizes Fasting Hyperglycemia and Improves Postprandial Glucose Tolerance in Totally Pancreatectomized Patients: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

OBJECTIVE: Insulin remains the only glucose-lowering treatment modality recommended for totally pancreatectomized patients. We investigated the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on fasting and postprandial glucose concentrations in pancreatectomized patients and matched healthy control participants. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled crossover study, 10 pancreatectomized patients and 10 matched control participants underwent two 3-h liquid mixed meal tests preceded by two doses of 25 mg empagliflozin (administered the night before and in the morning of the meal test) or placebo, respectively. Basal insulin was administered as usual, but bolus insulin was omitted before the meal test during experimental days. RESULTS: Compared with placebo, empagliflozin lowered fasting plasma glucose (5.0 ± 0.4 vs. 7.9 ± 0.9 mmol/L [mean ± SEM], P = 0.007) and postprandial plasma glucose excursions as assessed by baseline-subtracted area under the curve (1,080 [733; 1,231] vs. 1,169 [1,036; 1,417] pmol/L × min [median (25th and 75th percentiles)], P = 0.014) in the pancreatectomized patients. In the control participants, empagliflozin lowered fasting plasma glucose compared with placebo (5.1 ± 0.1 vs. 5.5 ± 0.1 mmol/L, P = 0.008) without affecting postprandial glucose excursions significantly. The pancreatomy group exhibited greater postprandial glucagon excursions compared with the control group on both experimental days (P ≤ 0.015); no within-group differences between days were observed. CONCLUSIONS: Empagliflozin administered the day before and immediately before a standardized liquid mixed meal test normalized fasting hyperglycemia and improved postprandial glucose tolerance in pancreatectomized patients.

Long-term results after resection of primary duodenal adenocarcinoma: A retrospective cohort study.

BACKGROUND: Radical resection of duodenal adenocarcinoma (DA) offers the possibility of cure. The outcome after operation and adjuvant therapy is mainly based on small numbers due to the low incidence of the disease. We examined the long-term outcome after surgical treatment of DA. MATERIAL AND METHODS: This was a retrospective cohort study including all patients undergoing curatively intended resection for histologically confirmed DA at a single University hospital. Long-term survival was examined by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding. RESULTS: A total of 96 patients were included. The median follow-up was 3.7 years (IQR 2.9-4.3), during which 18 patients (18.5%) had recurrence and 35 (36.5%) patients had died. The 3- and 5-year overall survival was 66.3% (55.6-76.9%) and 58.2% (46.2-70.2%), respectively. In the multivariable analysis, adjuvant therapy was associated with decreased mortality (HR 0.29, CI 0.11-0.76, P = 0.011) whereas positive lymph node ratio >0.20 was associated with increased mortality. CONCLUSION: Radical operation for DA has a median overall 5-year-survival of more than 50%. The indication for adjuvant chemotherapy remains to be addressed.

Glycemic Control and Variability of Diabetes Secondary to Total Pancreatectomy Assessed by Continuous Glucose Monitoring.

CONTEXT: The extent of the glycemic variability in diabetes secondary to total pancreatectomy is not fully understood. OBJECTIVE: To evaluate glycemic variability in totally pancreatectomized (PX) patients and compare it to glycemic variability in hemoglobin A1c (HbA1c)-matched patients with long-standing type 1 diabetes (T1D). DESIGN: A case-control study was performed. SETTING: Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. PATIENTS OR OTHER PARTICIPANTS: Ten PX patients (mean [SEM]: age 64.3 [9.8] years; body mass index (BMI) 34.4 [5.0] kg/m2; duration of diabetes 3 [2.8] years), 10 HbA1c-matched patients with T1D (63.9 [8.6] years; 24.6 [3.1] kg/m2; 22 [4] years), and 10 gender-, age-, and BMI-matched healthy controls. All patients were managed on multiple daily injections of insulin. INTERVENTION: Continuous glucose monitoring (CGM) (Medtronic MiniMed iPro 2) during 12 consecutive days. MAIN OUTCOME MEASURES: Glycemic variability. RESULTS: HbA1c levels were similar in the PX group and the T1D group. The PX group had greater continuous overall net glycemic action per 60 minutes (CONGA60 min) compared with the T1D group (mean [SEM]: 9.5 [0.3] vs 8.3 [0.2] mmol/L, P < 0.003) and mean plasma glucose values were higher in the PX group (10.6 [0.9] vs 9.0 [0.9] mmol/L, P < 0.001), whereas coefficient of variation for plasma glucose and standard deviation of mean plasma glucose, respectively, were similar in the 2 groups. Time spent below range was not different between the PX and the T1D group (2.3 [0.8] vs 4.5 [0.8]%, P = 0.065), whereas time spent above range was higher in the PX group (51.4 [3.3] vs 37.6 [1.9]%, P < 0.001). CONCLUSIONS: CGM-assessed glycemic variability showed higher CONGA60 min and time spent above range in our PX patients compared with HbA1c-matched T1D patients. This study is registered at www.ClinicalTrials.gov (NCT02944110).

Spontaneous intestinal bleeding due to pseudoaneurism of the gastroduodenal artery: case report of a rare complication to median arcuate ligament syndrome.

Median arcuate ligament syndrome (MALS) is the compression of the celiac artery (CA) by the median arcuate ligament. MALS can cause pseudoaneurysm of the gastroduodenal artery, which can lead to fatal bleeding. A 40-year-old male with no prior medical history presented with symptoms of upper gastrointestinal hemorrhage (UGIH). Severe duodenal bleeding was confirmed although endoscopic hemostasis was impossible and final hemostasis was achieved following a subsequent open duodenotomy. A postoperative computed tomographic angiography (CTA) visualized a significant CA stenosis, post-stenotic dilatation and an aneurysm on a jejunal branch artery. The patient underwent coiling of the gastroduodenal artery, gastroepiploic artery and two pancreaticoduodenal arterial branches. The patient was diagnosed with MALS and 6 months later underwent open resection of the median arcuate ligament. MALS should be considered as a rare cause of upper gastrointestinal bleeding. The literature and proposed treatments are discussed.

[Minimally invasive surgery for malignant diseases in pancreas].

Unlike most other abdominal procedures, pancreatic resection for malignant tumours is still predominantly performed as open surgery. However, recent published randomised trials suggest that a laparoscopic approach is safe and may offer advantages in the early postoperative period. Likewise, early reports of robot-assisted pancreatic resection suggest advantages. This reveiw describes the current status of minimally invasive pancreatic surgery for malignant tumours, including both laparoscopic and robot-assisted approaches for pancreaticoduodenectomy and distal pancreatectomy.

Preoperative TruCulture® whole blood cytokine response predicts post-operative inflammation in pancreaticoduodenectomy patients-A pilot cohort study.

Major surgery is associated with substantial morbidity and mortality with early post-operative adverse events (POAE) occurring in 30% of patients within the first 30 days. The underlying pathogenesis is multifactorial, including immune dysfunction and increased inflammatory response to surgery. We investigated preoperative immune function by the TruCulture® whole blood technique in a cohort of patients undergoing pancreaticoduodenectomy (PD), hypothesizing that patients developing inflammatory POAE defined as leucocytosis, fever or high (above median) area under the curve (AUC) C-reactive protein (CRP) the first post-operative week would display perturbed preoperative immune function. Sixty-two adult patients were screened, 30 included and 11 excluded post-inclusion due to other surgical procedures than PD and post-operative complications directly attributed to surgery, leaving 19 patients for analysis of preoperative immune function. Patients developing leucocytosis (n = 5, 26%) had lower Toll-like receptor (TLR)-3-stimulated IL-12p40 and higher Candida Albicans (TLR1/2/4/6, Dectin-1)-stimulated TNF-α, compared to patients without leucocytosis (all P < .05). Patients developing fever (n = 7, 37%) had lower TLR7/8-stimulated IFN-γ and patients with high AUC CRP (n = 9, 47%) had lower TLR3-stimulated IFN-γ and IL-6 and lower TLR7/8-stimulated IL-10 (all P < .05), compared to patients without fever or low CRP, respectively. In conclusion, patients with inflammatory POAE displayed lower preoperative stimulated IL-12p40, IFN-γ, IL-6 and IL-10 and higher TNF-α response, compared to patients without inflammatory POAE. This finding suggests that TruCulture is a feasible immunologic screening tool in surgical patients, with a potential for preoperative identification of patients at increased risk for inflammatory POAE, allowing for risk-based intervention trials.

The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial.

AIMS/HYPOTHESIS: Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. METHODS: In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 ± 9.5 mean±SD years; BMI: 22.9 ± 3.9 kg/m2) and 12 healthy control individuals (age 66.1 ± 7.6 years; BMI: 24.0 ± 2.9 kg/m2) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 µg of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. RESULTS: Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baseline-subtracted AUC [bsAUC] [mean±SEM]: 548 ± 125 vs 1447 ± 95 mmol/l × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51 mmol/l × min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 ± 1.0 mmol/l was reached at time point 134 ± 11 min with placebo, compared with a mean peak glucose concentration of 18 ± 1.4 mmol/l (p = 0.008) at time point 148 ± 13 min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 ± 0.4 mmol/l was reached at time point 70 ± 13 min with placebo, compared with a mean peak concentration of 5.5 ± 0.1 mmol/l (p < 0.001) at time point 8 ± 25 min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 ± 84 vs 1190 ± 311 pmol/l × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100 pmol/l × min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 ± 17 vs 189 ± 31 nmol/l × min, p < 0.001). CONCLUSIONS/INTERPRETATION: The GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon. TRIAL REGISTRATION: ClinicalTrials.gov NCT02640118. FUNDING: This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen.

Internal carotid artery blood flow is enhanced by elevating blood pressure during combined propofol-remifentanil and thoracic epidural anaesthesia: A randomised cross-over trial.

BACKGROUND: Anaesthesia reduces mean arterial pressure (MAP), and to preserve organ perfusion, vasopressors are often used to maintain MAP above 60 mmHg. Cognitive dysfunction is common following major surgery and may relate to intra-operative cerebral hypoperfusion. OBJECTIVE: The aim of this study was to evaluate whether internal carotid artery (ICA) blood flow increases when MAP is kept higher than 60 mmHg using noradrenaline. DESIGN: A randomised, cross-over trial. SETTING: Department of Anaesthesia, Rigshospitalet, Copenhagen, Denmark, from December 2017 to April 2018. PATIENTS: Patients with median [IQR] age 71 [63 to 75] years underwent pancreaticoduodenectomy (n = 19), total pancreatic resection (n = 1) or gastro-entero anastomosis (n = 2) during combined propofol-remifentanil and thoracic epidural anaesthesia. INTERVENTION: MAP was maintained between 60 to 65, 70 to 75 and 80 to 85 mmHg, in a random order, by noradrenaline infusion at a stable level of anaesthesia. MAIN OUTCOME MEASURES: Primary outcome was change in ICA flow at MAP 60 to 65 vs. 80 to 85 mmHg. Secondary outcomes were change in ICA flow at MAP 60 to 65 vs. 70 to 75 and 70 to 75 vs. 80 to 85 mmHg. Duplex ultrasound evaluated ICA flow. RESULTS: A (mean ± SD) increase in MAP from 62 ±â€Š1 to 82 ±â€Š1 mmHg elevated ICA flow from 196 ±â€Š53 to 226 ±â€Š61 ml min (mean difference 31 ml min; 95% CI 19 to 42; P < 0.0001). An increase in MAP from 62 ±â€Š1 to 72 ±â€Š1 mmHg elevated ICA flow to 210 ±â€Š52 ml min (P = 0.0271) and ICA flow increased further (P = 0.0165) when MAP was elevated to 82 ±â€Š1 mmHg. CONCLUSION: During combined propofol-remifentanil and thoracic epidural anaesthesia, ICA flow increased by approximately 15% when the MAP was elevated from about 60 to 80 mmHg. Treatment of a reduction in MAP brought about by anaesthesia seems to enhance ICA flow. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03309917.

Evidence of Extrapancreatic Glucagon Secretion in Man.

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.