procurement-parathyroid-glands-from-living-donor-pigs-ex-vivo

Procurement of Parathyroid Glands from Living Donor Pigs and <em>Ex Vivo</em> Identification

Hypoparathyroidism, often resulting from surgical complications, severely disrupts calcium homeostasis, leading to disabling symptoms. Current treatments ...

UNIVERSITY OF LILLE

Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.

Human Recombinant Antithrombin (ATryn) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model.

BACKGROUND AND STUDY AIMS : Endoscopic techniques have demonstrated their effectiveness in metabolic surgery, notably through a gastrointestinal (GI) liner, with a less invasive approach than conventional surgery. Our study evaluates the safety and efficacy of endoscopic GI anastomosis (EGIA) using a lumen-apposing stent to secure the anastomosis. MATERIALS AND METHODS : EGIA was performed using the transgastric approach with a two-channel endoscope with a novel stent (Cousin Biotech). First, a safety study with a follow-up of 12 months was performed on five piglets. Then, metabolic changes were investigated in a minipig model (n = 10) before and after EGIA or open GIA (OGIA).

Increased postprandial glucagon-like peptide-1 (GLP-1) production after endoscopic gastrointestinal bypass using the Cousin lumen-apposing stent in a porcine model.

The newest classes of anti-diabetic agents include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor (GLP1R) agonists. The SGLT2 inhibitor dapagliflozin reduces glucotoxicity by glycosuria but elevates glucagon secretion. The GLP1R agonist liraglutide inhibits glucagon; therefore, we hypothesize that the cotreatment of dapagliflozin with liraglutide could reduce hyperglucagonemia and hyperglycemia. Here we use five complementary models: human islet cultures, healthy mice, db/db mice, diet-induced obese (DIO) mice, and somatostatin receptor-2 (SSTR2) KO mice. A single administration of liraglutide and dapagliflozin in combination improves glycemia and reduces dapagliflozin-induced glucagon secretion in diabetic mice. Chronic treatment with liraglutide and dapagliflozin produces a sustainable reduction of glycemia compared with each drug alone. Moreover, liraglutide reduces dapagliflozin-induced glucagon secretion by enhancing somatostatin release, as demonstrated by SSTR2 inhibition in human islets and in mice. Collectively, these data provide mechanistic insights into how intra-islet GLP1R activation is critical for the regulation of glucose homeostasis.

The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release.

The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss. Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.

Characterization of one anastomosis gastric bypass and impact of biliary and common limbs on bile acid and postprandial glucose metabolism in a minipig model.

Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) , we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug.

Article	Year
Human Recombinant Antithrombin (ATryn) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model. Cell transplantation\| PubMed ID: 27938471	2017
Increased postprandial glucagon-like peptide-1 (GLP-1) production after endoscopic gastrointestinal bypass using the Cousin lumen-apposing stent in a porcine model. Endoscopy\| PubMed ID: 29195256	2018
The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release. Cell reports\| PubMed ID: 31390560	2019
Characterization of one anastomosis gastric bypass and impact of biliary and common limbs on bile acid and postprandial glucose metabolism in a minipig model. American journal of physiology. Endocrinology and metabolism\| PubMed ID: 33491532	2021
Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes. iScience\| PubMed ID: 36942050	2023

Audrey Quenon

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