Use of Hydroxocobalamin (Vitamin B12a) in Patients With Vasopressor Refractory Hypotension After Cardiopulmonary Bypass: A Case Series.

Hydroxocobalamin (vitamin B12a) is an emerging treatment for vasoplegic syndrome (VS) associated with cardiopulmonary bypass (CPB). Given its cost and scarcity, an institutional guideline for its use as a rescue treatment in cases of suspected VS was developed. Hemodynamic variables and vasopressor requirements were reviewed for a series of 24 post-CPB patients who received B12a. Favorable changes in hemodynamic parameters and vasopressor requirements were seen after B12a administration although guideline criteria for VS were inconsistently met. These findings support the continued study of B12a in patients with CPB-associated VS.

Metabolic regulation of glucagon secretion.

Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon's role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.

Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells.

Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from α-cells to stimulate hepatic glucose production. However, the mechanisms that regulate glucagon secretion from pancreatic α-cells remain unclear. Here we show that in α-cells, the interaction between fatty acid oxidation and glucose metabolism controls glucagon secretion. The glucose-dependent inhibition of glucagon secretion relies on pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity and lowering of mitochondrial fatty acid oxidation by increases in glucose. This results in reduced intracellular ATP and leads to membrane repolarization and inhibition of glucagon secretion. These findings provide a new framework for the metabolic regulation of the α-cell, where regulation of fatty acid oxidation by glucose accounts for the stimulation and inhibition of glucagon secretion. ARTICLE HIGHLIGHTS: It has become clear that dysregulation of glucagon secretion and α-cell function plays an important role in the development of diabetes, but we do not know how glucagon secretion is regulated. Here we asked whether glucose inhibits fatty acid oxidation in α-cells to regulate glucagon secretion. We found that fatty acid oxidation is required for the inhibitory effects of glucose on glucagon secretion through reductions in ATP. These findings provide a new framework for the regulation of glucagon secretion by glucose.

Sodium, Glucose and Dysregulated Glucagon Secretion: The Potential of Sodium Glucose Transporters.

Diabetes is defined by hyperglycaemia due to progressive insulin resistance and compromised insulin release. In parallel, alpha cells develop dysregulation of glucagon secretion. Diabetic patients have insufficient glucagon secretion during hypoglycaemia and a lack of inhibition of glucagon secretion at higher blood glucose levels resulting in postprandial hyperglucagonaemia, which contributes to the development of hyperglycaemia. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an efficient pharmacologic approach for the treatment of hyperglycaemia in type 2 diabetes. While SGLT2 inhibitors aim at increasing glycosuria to decrease blood glucose levels, these inhibitors also increase circulating glucagon concentrations. Here, we review recent advances in our understanding of how SGLTs are involved in the regulation of glucagon secretion. Sodium plays an important role for alpha cell function, and a tight regulation of intracellular sodium levels is important for maintaining plasma membrane potential and intracellular pH. This involves the sodium-potassium pump, sodium-proton exchangers and SGLTs. While the expression of SGLT2 in alpha cells remains controversial, SGLT1 seems to play a central role for alpha cell function. Under hyperglycaemic conditions, SGLT1 mediated accumulation of sodium results in alpha cell dysregulation due to altered cellular acidification and ATP production. Taken together, this suggests that SGLT1 could be a promising, yet highly underappreciated drug target to restore alpha cell function and improve treatment of both type 1 and 2 diabetes.

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet.

OBJECTIVES: Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD). METHODS: Female mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells were fed a high-fat or control (CTL) diet. We then conducted in vivo phenotyping of these mice, as well as experiments on isolated (ex vivo) islets and in the in situ perfused pancreas. RESULTS: In HFD-fed mice, fed plasma glucagon levels were increased and glucagon secretion from isolated islets and in the perfused mouse pancreas was also elevated. In mice fed a CTL diet, increasing glucose reduced intracellular Ca2+ ([Ca2+]i) oscillation frequency and amplitude. This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca2+]i oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD-fed mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca2+]i activity from HFD alpha-cells, in contrast to observations in CTL mice. CONCLUSIONS: These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cells including sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD.

Reduced Expression of the Co-regulator TLE1 in Type 2 Diabetes Is Associated with Increased Islet α-Cell Number.

ß-Cell dysfunction in type 2 diabetes (T2D) is associated with loss of cellular identity and mis-expression of alternative islet hormones, including glucagon. The molecular basis for these cellular changes has been attributed to dysregulation of core ß-cell transcription factors, which regulate ß-cell identity through activating and repressive mechanisms. The TLE1 gene lies near a T2D susceptibility locus and, recently, the glucagon repressive actions of this transcriptional coregulator have been demonstrated in vitro. We investigated whether TLE1 expression is disrupted in human T2D, and whether this is associated with increased islet glucagon-expressing cells. Automated image analysis following immunofluorescence in donors with (n = 7) and without (n = 7) T2D revealed that T2D was associated with higher islet α/ß cell ratio (Control: 0.7 ± 0.1 vs T2D: 1.6 ± 0.4; P < .05) and an increased frequency of bihormonal (insulin+/glucagon+) cells (Control: 0.8 ± 0.2% vs T2D: 2.0 ± 0.4%, P < .05). In nondiabetic donors, the majority of TLE1-positive cells were mono-hormonal ß-cells (insulin+/glucagon-: 98.2 ± 0.5%; insulin+/glucagon+: 0.7 ± 0.2%; insulin-/glucagon+: 1.1 ± 0.4%; P < .001). TLE1 expression was reduced in T2D (Control: 36 ± 2.9% vs T2D: 24 ± 2.6%; P < .05). Reduced islet TLE1 expression was inversely correlated with α/ß cell ratio (r = -0.55; P < .05). TLE1 knockdown in EndoC-ßH1 cells was associated with a 2.5-fold increase in glucagon gene mRNA and mis-expression of glucagon in insulin-positive cells. These data support TLE1 as a putative regulator of human ß-cell identity, with dysregulated expression in T2D associated with increased glucagon expression potentially reflecting ß- to α-cell conversion.

In Situ Analysis Reveals That CFTR Is Expressed in Only a Small Minority of ß-Cells in Normal Adult Human Pancreas.

CONTEXT: Although diabetes affects 40% to 50% of adults with cystic fibrosis, remarkably little is known regarding the underlying mechanisms leading to impaired pancreatic ß-cell insulin secretion. Efforts toward improving the functional ß-cell deficit in cystic fibrosis-related diabetes (CFRD) have been hampered by an incomplete understanding of whether ß-cell function is intrinsically regulated by cystic fibrosis transmembrane conductance regulator (CFTR). Definitively excluding meaningful CFTR expression in human ß-cells in situ would contribute significantly to the understanding of CFRD pathogenesis. OBJECTIVE: To determine CFTR messenger ribonucleic acid (mRNA) and protein expression within ß-cells in situ in the unmanipulated human pancreas of donors without any known pancreatic pathology. DESIGN: In situ hybridization for CFTR mRNA expression in parallel with insulin immunohistochemical staining and immunofluorescence co-localization of CFTR with insulin and the ductal marker, Keratin-7 (KRT7), were undertaken in pancreatic tissue blocks from 10 normal adult, nonobese deceased organ donors over a wide age range (23-71 years) with quantitative image analysis. RESULTS: CFTR mRNA was detectable in a mean 0.45% (range 0.17%-0.83%) of insulin-positive cells. CFTR protein expression was co-localized with KRT7. One hundred percent of insulin-positive cells were immunonegative for CFTR. CONCLUSIONS: For the first time, in situ CFTR mRNA expression in the unmanipulated pancreas has been shown to be present in only a very small minority (<1%) of normal adult ß-cells. These data signal a need to move away from studying endocrine-intrinsic mechanisms and focus on elucidation of exocrine-endocrine interactions in human cystic fibrosis.

Profound Obstructive Hypotension From Prone Positioning Documented by Transesophageal Echocardiography in a Patient With Scoliosis: A Case Report.

In a healthy 12-year-old female with scoliosis, prone positioning resulted in pressor-refractory cardiovascular collapse. Resumption of supine position immediately improved hemodynamics. Intraoperative transesophageal echocardiography (TEE) revealed a collapsed left atrium and biventricular failure. Repeat prone positioning resulted in a recurrence of hypotension. However, hemodynamic stabilization was restored and maintained by repositioning chest pads caudally. The patient successfully underwent a 6-hour scoliosis repair without perioperative morbidity. With this case, we aim to: (1) reintroduce awareness of this mechanical obstructive cause of reversible hypotension; (2) highlight the use of intraoperative TEE during prone hemodynamic collapse; and (3) suggest an alternative prone positioning technique if chest compression results in hemodynamic instability.

Point-of-care washing of allogeneic red blood cells for the prevention of transfusion-related respiratory complications (WAR-PRC): a protocol for a multicenter randomised clinical trial in patients undergoing cardiac surgery.

INTRODUCTION: The transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies with red blood cell (RBC) transfusion. Although mechanisms remain incompletely defined, soluble biological response modifiers (BRMs) within the RBC storage solution may play an important role. Point-of-care (POC) washing of allogeneic RBCs may remove these BRMs, thereby mitigating their impact on post-transfusion respiratory complications. METHODS AND ANALYSIS: This is a multicenter randomised clinical trial of standard allogeneic versus washed allogeneic RBC transfusion for adult patients undergoing cardiac surgery testing the hypothesis that POC RBC washing is feasible, safe, and efficacious and will reduce recipient immune and physiologic responses associated with transfusion-related respiratory complications. Relevant clinical outcomes will also be assessed. This investigation will enrol 170 patients at two hospitals in the USA. Simon's two-stage design will be used to assess the feasibility of POC RBC washing. The primary safety outcomes will be assessed using Wilcoxon Rank-Sum tests for continuous variables and Pearson chi-square test for categorical variables. Standard mixed modelling practices will be employed to test for changes in biomarkers of lung injury following transfusion. Linear regression will assess relationships between randomised group and post-transfusion physiologic measures. ETHICS AND DISSEMINATION: Safety oversight will be conducted under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained by the DSMB as well as the institutional review boards at each institution prior to enrolling the first study participant. This study aims to provide important information regarding the feasibility of POC washing of allogeneic RBCs and its potential impact on ameliorating post-transfusion respiratory complications. Additionally, it will inform the feasibility and scientific merit of pursuing a more definitive phase II/III clinical trial. REGISTRATION: ClinicalTrials.gov registration number is NCT02094118 (Pre-results).

Type A Dissection Involving Intimo-Intimal Intussusception Through the Aortic Valve.

The presentation, evaluation, management, and outcome of a case of type A circumferential dissection involving repeated retrograde intussusception of the intimal flap through the aortic valve is described in this case report. Fewer than 20 intimo-intimal intussusception cases have been described since the first report was published by Hufnagel in 1962, and outcomes have typically been poor because of delays in diagnosis. This case shows the potential for a positive outcome when the diagnosis of intimo-intimal intussusception is entertained and confirmed early in the course of treatment. Preoperative computed tomography and intraoperative transesophageal echocardiography were essential in diagnosis and operative planning.