The role of the glucagon-FGF21 axis in improving beta cell function during glucose intolerance and SGLT2 inhibition.

Objective: Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D).

Methods: FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques.

Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans.

Aims/hypothesis: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge.

The NERP-4-SNAT2 axis regulates pancreatic β-cell maintenance and function.

Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor.

Effects of subtotal pancreatectomy and long-term glucose and lipid overload on insulin secretion and glucose homeostasis in minipigs.

Introduction: Nowadays, there are no strong diabetic pig models, yet they are required for various types of diabetes research. Using cutting-edge techniques, we attempted to develop a type 2 diabetic minipig model in this study by combining a partial pancreatectomy (Px) with an energetic overload administered either orally or parenterally.

Methods: Different groups of minipigs, including Göttingen-like (GL, n = 17) and Ossabaw (O, n = 4), were developed.

The challenge of HLA donor specific antibodies in the management of pancreatic islet transplantation: an illustrative case-series.

Islet transplantation is a unique paradigm in organ transplantation, since multiple donors are required to achieve complete insulin-independence. Preformed or de novo Donor Specific Antibodies (DSA) may target one or several donor islets, which adds complexity to the analysis of their impact. Adult patients with type 1 diabetes transplanted with pancreatic islets between 2005 and 2018 were included in a single-center observational study.

Innovative transdermal delivery of insulin using gelatin methacrylate-based microneedle patches in mice and mini-pigs.

Painless and controlled on-demand drug delivery is the ultimate goal for the management of various chronic diseases, including diabetes. To achieve this purpose, microneedle patches are gaining increased attention. While degradable microneedle (MN) arrays are widely employed, the use of non-dissolving MN patches remains a challenge to overcome.

Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function.

Background And Aims: Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) is an endogenous inhibitor of the LDL receptor (LDLR). Mendelian randomization studies suggest that PCSK9 deficiency increases diabetes risk, but the underlying mechanisms remain unknown. The aim of our study was to investigate whether PCSK9 or its inhibition may modulate beta cell function.

Pancreatic islet transplantation under the kidney capsule of mice: model of refinement for molecular and graft analysis.

Diabetes cell therapy by human islet transplantation can restore an endogenous insulin secretion and normal glycaemic control in type 1 diabetic patients for as long as 10 years post transplantation. Before transplantation, each clinical islet preparation undergoes extensive and quality controls. The quality control assay consists of transplanting human islets under the kidney capsule of immunocompromised mice.

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

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.

Coxsackievirus-B4 Infection Can Induce the Expression of Human Endogenous Retrovirus W in Primary Cells.

Human Endogenous Retrovirus W Envelope (HERV-W ENV) mRNA or protein can be found in peripheral blood mononuclear cells (PBMCs) and exocrine pancreas of patients with type 1 diabetes (T1D). Further, previous observations have shown an association between enteroviral infection and development of T1D; specifically, coxsackievirus-B (CV-B) has been detected in the blood and pancreas of patients with T1D. Notably, viruses can activate HERV-W expression.

The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development.

Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm.

Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets.

Studies implicating sodium-glucose cotransporter 2 (SGLT2) inhibitors in glucagon secretion by pancreatic α-cells reported controversial results. We hypothesized that interindividual heterogeneity in SGLT2 expression and regulation may affect glucagon secretion by human α-cells in response to SGLT2 inhibitors. An unbiased RNA-sequencing analysis of 207 donors revealed an unprecedented level of heterogeneity of expression.

Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study.

Objective: The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft.

Research Design And Methods: We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK).

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

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.

Islets for Research: Nothing Is Perfect, but We Can Do Better.

In December 2018, and began requiring authors of papers reporting data obtained from studies on human islets to report critical characteristics of the human islets used for research. The islet community was asked to provide feedback on it. Here is the contribution by the European Consortium for Islet Transplantation.

Coxsackievirus-B4 Infection of Human Primary Pancreatic Ductal Cell Cultures Results in Impairment of Differentiation into Insulin-Producing Cells.

Coxsackievirus-B4 (CV-B4) E2 can persist in the pancreatic ductal-like cells (Panc-1 cell line), which results in an impaired differentiation of these cells into islet-like cell aggregates (ICA). In this study, primary pancreatic ductal cells obtained as a by-product of islet isolation from the pancreas of seven brain-dead adults were inoculated with CV-B4 E2, followed-up for 29 days, and the impact was investigated. Viral titers in culture supernatants were analyzed throughout the culture.

Single Low Dose of Human Recombinant Antithrombin (ATryn) has no Impact on Endotoxin-Induced Disseminated Intravascular Coagulation: An Experimental Randomized Open Label Controlled Study.

Background: Antithrombin (AT) III physiological levels are decreased during septic shock and supplementation therapy could therefore be beneficial.

Objective: We hypothesized that the use of recombinant human AT could reduce disseminated intravascular coagulation (DIC) occurrence.

Methods: We conducted a randomized open label controlled experimental study.

Safety of Islet Autotransplantation After Pancreatectomy for Adenocarcinoma.

Background: Total pancreatectomy with intraportal islet autotransplantation (TPIAT) rather than partial pancreatectomy could represent a major shift in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC) when risks of postoperative pancreatic fistula are well identified. This approach provides a theoretical risk of tumor cell dissemination when islet cells are transplanted into the portal vein. Our objective was to explore the safety of TPIAT in PDAC in a mouse preclinical model of subcutaneous xenotransplantation of human cells isolated from pancreatic specimen during partial pancreatectomy performed for PDAC.

Comparison of fluid balance and hemodynamic and metabolic effects of sodium lactate versus sodium bicarbonate versus 0.9% NaCl in porcine endotoxic shock: a randomized, open-label, controlled study.

Background: Sodium lactate has been shown to improve hemodynamics and avoid fluid overload. The objective of this study was to confirm a beneficial effect on fluid balance with sodium lactate infusion and to specify whether the advantage of lactate is related to a negative chloride balance, its particular metabolism, or simply its energy load.

Methods: This was an interventional, randomized, open-label, controlled experimental study.

Pharmacological approach to understanding the control of insulin secretion in human islets.

Aims: To understand better the control of insulin secretion by human β cells and to identify similarities to and differences from rodent models.

Methods: Dynamic insulin secretion was measured in perifused human islets treated with pharmacological agents of known modes of action.

Results: Glucokinase activation (Ro28-1675) lowered the glucose threshold for stimulation of insulin secretion to 1 mmol/L (G1), augmented the response to G3-G5 but not to G8-G15, whereas tolbutamide remained active in G20, which indicates that not all K channels were closed by high glucose concentrations.

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

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).

Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL.

Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells.