Gluco-metabolic response to exogenous oxytocin in totally pancreatectomized patients and healthy individuals.

Oxytocin has been proposed to possess glucose-stabilizing effects through the release of insulin and glucagon from the pancreas. Also, exogenous oxytocin has been shown to stimulate extrapancreatic glucagon secretion in depancreatized dogs. Here, we investigated the effect of exogenous oxytocin on circulating levels of pancreatic and gut-derived glucose-stabilizing hormones (insulin [measured as C-peptide], glucagon, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic polypeptide). We studied nine pancreatectomized (PX) patients and nine healthy controls (CTRLs) (matched on age and body mass index) before, during, and after an intravenous infusion of 10 IU of oxytocin administered over 12 min. Oxytocin did not increase plasma glucagon levels, nor induce any changes in plasma glucose, C-peptide, or GIP in any of the groups. Oxytocin decreased plasma glucagon levels by 19 ± 10 % in CTRLs (from 2.0 ± 0.5 [mean ± SEM] to 1.3 ± 0.2 pmol/l, P = 0.0025) and increased GLP-1 by 42 ± 22 % in PX patients (from 9.0 ± 1.0-12.7 ± 1.0 pmol/l, P = 0.0003). Fasting plasma glucose levels were higher in PX patients compared with CTRLs (13.1 ± 1.1 vs. 5.1 ± 0.1 mmol/l, P < 0.0001). In conclusion, the present findings do not support pancreas-mediated glucose-stabilizing effects of acute oxytocin administration in humans and warrant further investigation of oxytocin's gluco-metabolic effects.

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).

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.