Severe bradycardia and hypotension in anaesthetized pigs: Possible interaction between octreotide, xylazine, and atropine: A case series

Pigs are common animal models in diabetes research. Streptozotocin-induced destruction of pancreatic β-cells is used to induce diabetes in conscious pigs. However, in short-term non-recovery experiments, suppression of endogenous insulin secretion can be faster and more easily achieved with somatostatin analogues. We report a series of severe and unexpected episodes of severe bradycardia in eight pigs during non-recovery experiments with the original aim of investigating the pharmacokinetics and pharmacodynamics of intraperitoneal hormone delivery. The adverse events occurred four to five hours into the experiments, and we believe that they were caused by an interaction between the somatostatin analogue octreotide, and the sedative drug xylazine and that atropine delayed the time of occurrence

The intraperitoneal artificial pancreas: glucose sensing and glucagon delivery

Norsk sammendrag Diabetes er en gruppe sykdommer som globalt rammer millioner av mennesker. Denne avhandlingen fokuserer på diabetes mellitus type 1 som kjennetegnes av ingen, eller veldig liten, produksjon av insulin. Diabetes mellitus type 1 var en dødelig sykdom frem til 1922, da den første pasienten mottok behandling med eksternt tilført insulin. Selv om behandlingen av DM1 har gjennomgått en revolusjonærene utvikling det siste århundret, opplever mange pasienter alvorlige bivirkninger på grunn av suboptimal glukoseregulering til tross for at de investerer mye tid og krefter i sin håndtering av sykdommen. En kunstig bukspyttkjertel er en teknisk innretning som automatiserer tilførselen av insulin og på den måte holder blodglukosenivået nær normale nivåer og på den åten unngå bivirkningene av sykdommen. Det kunstige bukspyttkjertelen bør også avlaste brukeren fra den kontinuerlige oppmerksomheten personer med diabetes mellitus type 1 må ha til sin sykdom. Det første kunstige bukspyttkjertelsystemet ble godkjent av the United States Food and Drug Administration og gjort tilgjengelige for pasienter i 2016. Systemet er et såkalt dobbelt-subkutant, det vil si at både glukosemålinger og tilførsel av insulin skjer i underhuden. Systemet er ikke fullt automatisert system, da det kun justerer den basale insulininfusjonen, og er ikke i stand til å unngå den typisk store økningen i blodglukose etter et måltid. Denne hybridløsningen er derfor avhengig av at brukerne informerer systemet om alle kommende inntak av karbohydrater slik at insulin kan doseres i forkant av måltider. En kunstig bukspyttkjertel er et lukket sløyfesystem som består av en glukosesensor, en hormonpumpe (eller flere pumper for systemer med flere hormoner) og en kontroller. Kontrolleren bestemmer hvilket og hvor mye hormon som skal administreres basert på målinger fra glukosesensoren. Systemet er avhengig av minimale forsinkelser i alle deler av sløyfen for å fungere kunne oppfylle intensjonen om å være et full-automatisert system. Fysiologiske forsinkelser observeres for både glukosemålinger og hormoneffekt, og forsinkelsen i insulinets effekt på glukosestoffskiftet er den største utfordringen for de systemene som benytter underhuden både til glukosemåling og insulintilførsel. Bukhulen blir av den grunn undersøkt som et alternativt sted for en kunstig bukspyttkjertel fordi tidligere studier har vist rask dynamikk både for hormoneffekt og glukosemålinger. Hovedmålet med denne avhandlingen var å undersøke glukosemåling og administrering av glukagon i bukhulen som en del av en kunstig bukspyttkjertel. Den første artikkelen undersøkte potensielle forskjeller i glukosedynamikk avhengig av lokalisasjon i bukhulen hos anesteserte griser. Det ser ikke ut til å være noen klinisk signifikante forskjeller i glukosedynamikk mellom de fire kvadrantene av bukhulen. Den andre artikkelen i avhandlingen diskuterer betydningen av å måle glukose så nært peritonealhinnen som mulig for å oppnå tilstrekkelig raske målinger av forandringer i blodglukosenivået. De to siste artiklene undersøkte effekten på blodglukosenivåene etter administrering av glukagon i bukhulen og sammenlignet dette med administrering av glukagon i underhuden. Resultatene viste at glukoseresponsen var raskere etter administrering i bukhulen på rotter og ga en høyere glukoserespons hos anesteserte griser sammenlignet med administrering i underhuden. Resultatene viser også at tilstrekkelige økninger i blodglukose kan oppnås ved bruk av mindre doser ved intraperitoneal sammenlignet med subkutan administrering. Dette kan medføre at bivirkninger av glukagonbehandlingen kan unngås ved intraperitoneal administrering av glukagon. Denne avhandlingen viser at bukhulen er et lovende sted for måling av glukose og administrering av glukagon som en del av en kunstig bukspyttkjertel. Imidlertid må optimal sensorteknologi utvikles og ytterligere dyreforsøk utføres før man kan avgjøre om en dobbelt intraperitoneal kunstig bukspyttkjertel er en mulig framtidig behandlingsløsning for personer med diabetes mellitus type 1

Pharmacokinetics of Intraperitoneally Delivered Glucagon in Pigs: A Hypothesis of First Pass Metabolism

Background and Objective Artificial pancreases administering low-dose glucagon in addition to insulin have the scope to improve glucose control in patients with diabetes mellitus type 1. If such a device were to deliver both hormones intraperitoneally, it would mimic normal physiology, which may be beneficial. However, the pharmacokinetic properties of glucagon after intraperitoneal administration are not well known. Hence, the current study aims to evaluate the relationship between the amount of intraperitoneally delivered glucagon and pharmacokinetic variables in a pig model. Methods Pharmacokinetic data was retrieved from experiments on 19 anaesthetised pigs and analysed post hoc. The animals received a single intraperitoneal bolus of glucagon ranging from 0.30 to 4.46 µg/kg. Plasma glucagon was measured every 2–10 min for 50 min. Results Peak plasma concentration and area under the time–plasma concentration curve of glucagon correlated positively with the administered dose, and larger boluses provided a relatively greater increase. The mean (standard deviation) time to maximum glucagon concentration in plasma was 11 (5) min, and the mean elimination half-life of glucagon in plasma was 19 (7) min. Conclusions Maximum plasma concentration and area under the time–plasma concentration curve of glucagon increase nonlinearly in relation to the intraperitoneally administered glucagon dose. We hypothesise that the results are compatible with a satiable first-pass metabolism in the liver. Time to maximum glucagon concentration in plasma and the elimination half-life of glucagon in plasma seem independent of the drug dose

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: A randomized controlled crossover trial

Objective Hypoglycemia is a frequent and potentially dangerous event among patients with diabetes mellitus type 1. Subcutaneous glucagon is an emergency treatment to counteract severe hypoglycemia. The effect of intraperitoneal glucagon delivery is sparsely studied. We performed a direct comparison of the blood glucose response following intraperitoneally, subcutaneously and intravenously administered glucagon. Research design and methods This is a prospective, randomized, controlled, open-label, crossover trial in 20 octreotide-treated rats. Three interventions, 1  week apart, in a randomized order, were done in each rat. All 20 rats were given intraperitoneal and subcutaneous glucagon injections, from which 5 rats were given intravenous glucagon injections and 15 rats received placebo (intraperitoneal isotonic saline) injection. The dose of glucagon was 5 µg/kg body weight for all routes of administration. Blood glucose levels were measured before and until 60 min after the glucagon/placebo injections. Results Compared with placebo-treated rats, a significant increase in blood glucose was observed 4 min after intraperitoneal glucagon administration (p=0.009), whereas after subcutaneous and intravenous glucagon administration significant increases were seen after 8 min (p=0.002  and p<0.001, respectively). In intraperitoneally treated compared with subcutaneously treated rats, the increase in blood glucose was higher after 4 min (p=0.019) and lower after 40 min (p=0.005) and 50 min (p=0.011). The maximum glucose response occurred earlier after intraperitoneal compared with subcutaneous glucagon injection (25 min vs 35 min; p=0.003). Conclusions Glucagon administered intraperitoneally gives a faster glucose response compared with subcutaneously administered glucagon in rats. If repeatable in humans, the more rapid glucose response may be of importance in a dual-hormone artificial pancreas using the intraperitoneal route for administration of insulin and glucagon

Intraperitoneal and subcutaneous glucagon delivery in anaesthetized pigs: effects on circulating glucagon and glucose levels

Glucagon is a pancreatic hormone and increases the blood glucose levels. It may be incorporated in a dual hormone artificial pancreas, a device to automatically and continuously control blood glucose levels of individuals with diabetes. Artificial pancreas systems have been developed for use in the subcutaneous tissue; however, the systems are not fully automated due to slow dynamics. The intraperitoneal space is therefore investigated as an alternative location for an artificial pancreas. Glucose dynamics after subcutaneous and intraperitoneal glucagon delivery in ten anaesthetized pigs were investigated. The pigs received intraperitoneal boluses of 0.3 µg/kg and 0.6 µg/kg and a subcutaneous bolus of 0.6 µg/kg in randomized order. They also received an intraperitoneal bolus of 1 mg given at the end of the experiments to test the remaining capacity of rapid glucose release. Six pigs were included in the statistical analysis. The intraperitoneal glucagon bolus of 0.6 µg/kg gave a significantly higher glucose response from 14 to 30 min compared with the subcutaneous bolus. The results indicate that glucagon induces a larger glucose response after intraperitoneal delivery compared with subcutaneous delivery and is encouraging for the incorporation of glucagon in an intraperitoneal artificial pancreas

Intraperitoneal, subcutaneous and intravenous glucagon delivery and subsequent glucose response in rats: A randomized controlled crossover trial

Objective Hypoglycemia is a frequent and potentially dangerous event among patients with diabetes mellitus type 1. Subcutaneous glucagon is an emergency treatment to counteract severe hypoglycemia. The effect of intraperitoneal glucagon delivery is sparsely studied. We performed a direct comparison of the blood glucose response following intraperitoneally, subcutaneously and intravenously administered glucagon. Research design and methods This is a prospective, randomized, controlled, open-label, crossover trial in 20 octreotide-treated rats. Three interventions, 1  week apart, in a randomized order, were done in each rat. All 20 rats were given intraperitoneal and subcutaneous glucagon injections, from which 5 rats were given intravenous glucagon injections and 15 rats received placebo (intraperitoneal isotonic saline) injection. The dose of glucagon was 5 µg/kg body weight for all routes of administration. Blood glucose levels were measured before and until 60 min after the glucagon/placebo injections. Results Compared with placebo-treated rats, a significant increase in blood glucose was observed 4 min after intraperitoneal glucagon administration (p=0.009), whereas after subcutaneous and intravenous glucagon administration significant increases were seen after 8 min (p=0.002  and p<0.001, respectively). In intraperitoneally treated compared with subcutaneously treated rats, the increase in blood glucose was higher after 4 min (p=0.019) and lower after 40 min (p=0.005) and 50 min (p=0.011). The maximum glucose response occurred earlier after intraperitoneal compared with subcutaneous glucagon injection (25 min vs 35 min; p=0.003). Conclusions Glucagon administered intraperitoneally gives a faster glucose response compared with subcutaneously administered glucagon in rats. If repeatable in humans, the more rapid glucose response may be of importance in a dual-hormone artificial pancreas using the intraperitoneal route for administration of insulin and glucagon.publishedVersion© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

Physiological effects of intraperitoneal versus subcutaneous insulin infusion in patients with diabetes mellitus type 1: A systematic review and meta-analysis

The intraperitoneal route of administration accounts for less than 1% of insulin treatment regimes in patients with diabetes mellitus type 1 (DM1). Despite being used for decades, a systematic review of various physiological effects of this route of insulin administration is lacking. Thus, the aim of this systematic review was to identify the physiological effects of continuous intraperitoneal insulin infusion (CIPII) compared to those of continuous subcutaneous insulin infusion (CSII) in patients with DM1. Four databases (EMBASE, PubMed, Scopus and CENTRAL) were searched beginning from the inception date of each database to 10th of July 2020, using search terms related to intraperitoneal and subcutaneous insulin administration. Only studies comparing CIPII treatment (≥ 1 month) with CSII treatment were included. Primary outcomes were long-term glycaemic control (after ≥ 3 months of CIPII inferred from glycated haemoglobin (HbA1c) levels) and short-term (≥ 1 day for each intervention) measurements of insulin dynamics in the systematic circulation. Secondary outcomes included all reported parameters other than the primary outcomes. The search identified a total of 2242 records; 39 reports from 32 studies met the eligibility criteria. This meta-analysis focused on the most relevant clinical end points; the mean difference (MD) in HbA1c levels during CIPII was significantly lower than during CSII (MD = -6.7 mmol/mol, [95% CI: -10.3 –-3.1]; in percentage: MD = -0.61%, [95% CI: -0.94 –- 0.28], p = 0.0002), whereas fasting blood glucose levels were similar (MD = 0.20 mmol/L, [95% CI: -0.34–0.74], p = 0.47; in mg/dL: MD = 3.6 mg/dL, [95% CI: -6.1–13.3], p = 0.47). The frequencies of severe hypo- and hyper-glycaemia were reduced. The fasting insulin levels were significantly lower during CIPII than during CSII (MD = 16.70 pmol/L, [95% CI: -23.62 –-9.77], p < 0.0001). Compared to CSII treatment, CIPII treatment improved overall glucose control and reduced fasting insulin levels in patients with DM1

Intraperitoneal insulin administration in pigs: Effect on circulating insulin and glucose levels

Introduction The effect of intraperitoneal insulin infusion has limited evidence in the literature. Therefore, the aim of the study was to investigate the pharmacokinetics and pharmacodynamics of different intraperitoneal insulin boluses. There is a lack of studies comparing the insulin appearance in the systemic circulation after intraperitoneal compared with subcutaneous insulin delivery. Thus, we also aimed for a comparison with the subcutaneous route. Research design and methods Eight anesthetized, non-diabetic pigs were given three different intraperitoneal insulin boluses (2, 5 and 10 U). The order of boluses for the last six pigs was randomized. Endogenous insulin and glucagon release were suppressed by repeated somatostatin analog injections. The first pig was used to identify the infusion rate of glucose to maintain stable glucose values throughout the experiment. The estimated difference between insulin boluses was compared using two-way analysis of variance (GraphPad Prism V.8). In addition, a trial of three pigs which received subcutaneous insulin boluses was included for comparison with intraperitoneal insulin boluses. Results Decreased mean blood glucose levels were observed after 5 and 10 U intraperitoneal insulin boluses compared with the 2 U boluses. No changes in circulating insulin levels were observed after the 2 and 5 U intraperitoneal boluses, while increased circulating insulin levels were observed after the 10 U intraperitoneal boluses. Subcutaneously injected insulin resulted in higher values of circulating insulin compared with the corresponding intraperitoneal boluses. Conclusions Smaller intraperitoneal boluses of insulin have an effect on circulating glucose levels without increasing insulin levels in the systemic circulation. By increasing the insulin bolus, a major increase in circulating insulin was observed, with a minor additive effect on circulating glucose levels. This is compatible with a close to 100% first-pass effect in the liver after smaller intraperitoneal boluses. Subcutaneous insulin boluses markedly increased circulating insulin levels

Why intraperitoneal glucose sensing is sometimes surprisingly rapid and sometimes slow: A hypothesis

The artificial pancreas requires fast and reliable glucose measurements. The peritoneal space has shown promising results, and in one of our studies we detected glucose changes in the peritoneal space already at the same time as in the femoral artery. The peritoneal lining is highly vascularised, covered by a single layer of mesothelial cells and therefore easily accessible for proper sensor technology, e.g. optical technology. We hypothesize that the rapid intraperitoneal glucose dynamics observed in our study was possible because the sensors were located directly at the peritoneal lining, at the point where the glucose molecules entered the peritoneal space. Glucose travels slowly in fluids by diffusion, and a longer distance between the sensor and the peritoneal lining would consequently result in slower dynamics. We therefore propose to place the glucose sensor in an artificial pancreas as closely to the peritoneal lining as possible, or even utilize appropriate sensor technology to measure glucose in the peritoneal lining itself