10 results found
Akalestou E, Suba K, Lopez-Noriega L, et al., 2021, Intravital imaging of islet Ca2+ dynamics reveals enhanced beta cell connectivity after bariatric surgery in mice, NATURE COMMUNICATIONS, Vol: 12
Akalestou E, Miras A, Rutter G, et al., 2021, Mechanisms of weight loss after obesity surgery, Endrocrine Reviews
Obesity surgery remains the most effective treatment for obesity and its complications.Weight loss was initially attributed to decreased energy absorption from the gut buthave since been linked to reduced appetitive behaviour and potentially increasedenergy expenditure. Implicated mechanisms associating rearrangement of thegastrointestinal tract with these metabolic outcomes include central appetite control,release of gut peptides, change in microbiota and bile acids. However, the exactcombination and timing of signals remain largely unknown. In this review, we surveyrecent research investigating these mechanisms, and seek to provide insights onunanswered questions over how weight loss is achieved following bariatric surgerywhich may eventually lead to safer, nonsurgical weight-loss interventions orcombinations of medications with surgery
Muniangi-Muhitu H, Akalestou E, Salem V, et al., 2020, Covid-19 and diabetes: a complex bidirectional relationship, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392
Covid-19 is a recently-emerged infectious disease caused by the novel severe acute respiratory syndrome coronavirus SARS-CoV2. SARS-CoV2 differs from previous coronavirus infections (SARS and MERS) due to its high infectivity (reproduction value, R0, typically 2-4) and pre- or asymptomatic transmission, properties that have contributed to the current global Covid-19 pandemic. Identified risk factors for disease severity and death from SARS-Cov2 infection include older age, male sex, diabetes, obesity and hypertension. The reasons for these associations are still largely obscure. Evidence is also emerging that SARS-CoV2 infection exacerbates the underlying pathophysiology of hyperglycemia in people with diabetes. Here, we discuss potential mechanisms through which diabetes may affect the risk of more severe outcomes in Covid-19 and, additionally, how diabetic emergencies and longer term pathology may be aggravated by infection with the virus. We consider roles for the immune system, the observed phenomenon of microangiopathy in severe Covid-19 infection and the potential for direct viral toxicity on metabolically-relevant tissues including pancreatic beta cells and targets of insulin action.
Akalestou E, Suba K, Lopez-Noriega L, et al., 2020, Intravital imaging of islet Ca2+ dynamics reveals enhanced β cell connectivity after bariatric surgery in mice
<jats:title>Abstract</jats:title><jats:p>Bariatric surgery improves both insulin sensitivity and secretion in type 2 diabetes. However, these changes are difficult to monitor directly and independently. In particular, the degree and the time course over which surgery impacts β cell function, versus mass, have been difficult to establish. In this study, we investigated the effect of bariatric surgery on β cell function <jats:italic>in vivo</jats:italic> by imaging Ca<jats:sup>2+</jats:sup> dynamics prospectively and at the single cell level in islets engrafted into the anterior eye chamber. Islets expressing GCaMP6f selectively in the β cell were transplanted into obese male hyperglycaemic mice that were then subjected to either vertical sleeve gastrectomy (VSG) or sham surgery. Imaged <jats:italic>in vivo</jats:italic> in the eye, VSG improved coordinated Ca<jats:sup>2+</jats:sup> activity, with 90% of islets observed exhibiting enhanced Ca<jats:sup>2+</jats:sup> wave activity ten weeks post-surgery, while islet wave activity in sham animals fell to zero discernible coordinated islet Ca<jats:sup>2+</jats:sup> activity at the same time point. Correspondingly, VSG mice displayed significantly improved glucose tolerance and insulin secretion. Circulating fasting levels of GLP-1 were also increased after surgery, potentially contributing to improved β cell performance. We thus demonstrate that bariatric surgery leads to time-dependent increases in individual β cell function and intra-islet connectivity, together driving increased insulin secretion and diabetes remission, in a weight-loss independent fashion.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>Used widely to treat obesity, bariatric surgery also relieves the symptoms of type 2 diabetes. The mechanisms involved in diabetes remission are still
Akalestou E, Genser L, Rutter GA, 2020, Glucocorticoid metabolism in obesity and following weight loss, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392
Glucocorticoids are steroid hormones produced by the adrenal cortex and are essential for the maintenance of various metabolicand homeostatic functions. Their function is regulated at the tissue level by 11β‐hydroxysteroid dehydrogenases and they signalthrough the glucocorticoid receptor, a ligand-dependent transcription factor. Clinical observations have linked excess glucocorticoidlevels with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance anddyslipidaemia. In this review, we discuss the physiological mechanisms of glucocorticoid secretion, regulation and function, andsurvey the metabolic consequences of excess glucocorticoid action resulting from elevated release and activation or up-regulatedsignalling. Finally, we summarise the reported impact of weight loss by diet, exercise or bariatric surgery on circulating andtissue-specific glucocorticoid levels and examine the therapeutic possibility of reversing glucocorticoid-associated metabolicdisorders.
McGrath T, Spreckley E, Rodriguez A, et al., 2019, The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents, PLoS Biology, Vol: 17, Pages: 1-30, ISSN: 1544-9173
Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that capturesthe complexity of feeding behaviour. We construct an accurate stochasticmodel of rodent feeding at the bout level in order to perform quantitativebehavioural analysis. Analysing the different effects on feeding behaviour ofPYY3-36, lithium chloride, GLP-1 and leptin shows the precise behaviouralchanges caused by each anorectic agent. Our analysis demonstrates that thechanges in feeding behaviour evoked by the anorectic agents investigated donot mimic the behaviour of well-fed animals, and that the intermeal intervalis influenced by fullness. We show how robust homeostatic control of feedingthwarts attempts to reduce food intake, and how this might be overcome. Insilico experiments suggest that introducing a minimum intermeal interval ormodulating upper gut emptying can be as effective as anorectic drug administration.
Akalestou E, Genser L, Villa F, et al., 2018, Establishing a successful rat model of duodenal- jejunal bypass: A detailed guide, Laboratory Animals, ISSN: 0023-6772
Murphy KG, Spreckley E, Norton M, et al., 2017, L-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium sensing receptor in rodents, International Journal of Obesity, Vol: 41, Pages: 1693-1701, ISSN: 1476-5497
Objectives: High protein diets are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which high protein diets exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may play a role in appetite regulation and satiety. We investigated the effects of L-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents.Methods: We investigated the effects of the aromatic amino acid and calcium sensing receptor (CaSR) agonist L-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral L-Phe administration on glucose tolerance in rats. Results: Oral administration of L-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal L-Phe also reduced food intake in rats. L-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal L-Phe in rats, and L-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade.Conclusions: L-Phe reduced food intake, stimulated GLP-1 and PYY release and reduced plasma ghrelin in rodents. Our data provides evidence that the anorectic effects of L-Phe are mediated via the CaSR, and suggest that L-Phe and the CaSR system in the gastrointestinal tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.
Hussain MA, Akalestou E, Song W-J, 2016, Inter-organ communication and regulation of beta cell function, Diabetologia, Vol: 59, Pages: 659-667, ISSN: 0012-186X
The physiologically predominant signal for pancreaticbeta cells to secrete insulin is glucose. While circulatingglucose levels and beta cell glucose metabolism regulate theamount of released insulin, additional signals emanating fromother tissues and from neighbouring islet endocrine cells modulatebeta cell function. To this end, each individual beta cellcan be viewed as a sensor of a multitude of stimuli that areintegrated to determine the extent of glucose-dependent insulinrelease. This review discusses recent advances in our understandingof inter-organ communications that regulate betacell insulin release in response to elevated glucose levels.
Akalestou E, Christakis I, Solomou A, et al., 2016, Proglucagon-derived peptides do not significantly affect acute exocrine pancreas in rat, Pancreas, Vol: 45, Pages: 967-973, ISSN: 1536-4828
Objectives: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogues and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential anti-obesity therapy, but little is known about the pancreatic safety of this approach. The aim of this study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. Methods: GLP-1, oxyntomodulin, glucagon and exendin-4 were infused into anaesthetised rats to measure plasma amylase concentration changes. Additionally, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. Results: Plasma amylase did not increase post infusion of individual peptides, compared to vehicle and cholecystokinin (CCK); however, oxyntomodulin inhibited plasma amylase when co-administered with CCK. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. Conclusions: the investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin appears to be a potent inhibitor of amylase release, potentially making it a safer anti-obesity agent regarding pancreatitis, compared to GLP-1 agonists.
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