20 results found
Akalestou E, Lopez-Noriega L, Christakis I, et al., 2022, Vertical Sleeve Gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice, Frontiers in Endocrinology, ISSN: 1664-2392
Objectives: Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis.Glucocorticoid activation is catalysed by 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1). Excess glucocorticoids are associatedwith insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism ofbariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumedto result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgerycontributes to the widely observed euglycemic effects of the treatment. Methods: Glucose and insulin tolerance tests wereperformed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvestedfrom fed mice and 11β‐HSD1 levels were measured by quantitative RT‐PCR or Western (immuno‐) blotting, respectively. 11β‐HSD1null mice (Hsd11b1-/-) were generated using CRISPR/ Cas9 genome editing. Wild type (WT) and littermate Hsd11b1-/- miceunderwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Results: WT VSG-treated mice displayed significantly improvedglucose tolerance versus sham controls, and this effect was observed in both regular chow- and HFD-fed animals. VSG lowered bodyweight in HFD but not regular chow-fed mice. Remarkably, VSG restored physiological corticosterone production in HFD mice andreduced 11β‐HSD1 expression in liver and adipose tissue post‐surgery. Elimination of the 11β‐HSD1/Hsd11b1 gene mimicked theeffects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at 3 g/kg glucose, the impact of VSG on glucoseexcursion was indistinguishable between WT and Hsd11b1-/- mice, suggesting that the euglycemic effect of VSG was superior toHsd11b1 elimination. Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoi
Jones B, Burade V, Akalestou E, et al., 2022, In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist, DIABETES OBESITY & METABOLISM, ISSN: 1462-8902
Akalestou E, Lopez-Noriega L, Tough IR, et al., 2022, Vertical sleeve gastrectomy lowers SGLT2/Slc5a2 expression in the mouse kidney, Diabetes, Vol: 71, ISSN: 0012-1797
Bariatric surgery improves glucose homeostasis but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium glucose cotransporter-2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by CRISPR/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2 null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2 null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose lowering effects of bariatric surgery.
Georgiadou E, Muralidharan C, Martinez M, et al., 2022, Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated beta cell connectivity and insulin secretion, Diabetes, Vol: 71, Pages: 1472-1489, ISSN: 0012-1797
Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitofusin gene expression, and hence mitochondrial network integrity, is important for glucose or incretin signalling has not previously been explored. Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia and a >five-fold decrease in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis, cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2 dKO mice and GLP-1 or GIP receptor agonists largely corrected defective GSIS through enhanced EPAC-dependent signalling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta cells, the potential contributions of altered mitochondrial dynamics to diabetes development and the impact of incretins on this process.
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
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 (vol 12, 5165, 2021), Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723
Slieker RC, Donnelly LA, Lopez-Noriega L, et al., 2021, Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study, Publisher: SPRINGER, Pages: 108-108, ISSN: 0012-186X
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, Pages: 1-13, ISSN: 2041-1723
Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on β cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on β cell function in vivo by imaging Ca2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented β cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the β cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in β cell function and intra-islet connectivity which are likely to contribute to diabetes remission.
Georgiadou E, Muralidharan C, Martinez M, et al., 2021, Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion, bioRxiv
Aims/hypothesis Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitochondrial networks may be important for glucose or incretin sensing has yet to be determined.Methods Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). Whole or dissociated pancreatic islets were used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production or GSIS in response to increasing glucose concentrations or GLP-1 receptor agonists. Serum and blood samples were collected to examine oral and i.p. glucose tolerance.Results βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia (p<0.01, p<0.001) and a >five-fold decrease (p<0.0001) in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis and cytosolic Ca2+ increases were all reduced (p<0.05,p<0.01,p<0.0001) in dKO islets, and beta cell Ca2+ dynamics were suppressed in vivo (p<0.001). In contrast, oral glucose tolerance was near normal in βMfn1/2 dKO mice (p<0.05, p<0.01) and GLP-1 or GIP receptor agonists largely corrected defective GSIS from isolated islets through an EPAC-dependent signalling activation.Conclusions/interpretation Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. Defects in these cycles in some forms of diabetes might therefore provide opportunities for novel incretin-based or other therapies.Impact of Mfn1/2 deletion on glucose and incretin stimulated-insulin secretion in beta cells. (A) In control animals, glucose is taken up by beta cells through GLUT2 and metabolised by mitochondria (elongated structure) through the citrate (TCA) cycle, leading to an increased mitochondrial proton motive force (hyperpolarised Δψm), accelerated
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, Lopez-Noriega L, Christakis I, et al., 2020, Bariatric surgery normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. Glucocorticoid activation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Lean mice and HFD mice underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Glucose and insulin tolerance tests were performed at four and ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested from fed mice and 11β-HSD1 and GR levels were measured by quantitative RT-PCR or Western (immuno-) blotting, respectively.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>VSG did not cause excess weight loss in lean mice when compared to sham operated mice. However, both lean and HFD VSG mice displayed significantly improved glucose clearance and insulin sensitivity. Remarkably, VSG restores physiological corticosterone production in HFD mice and reduces11β-HSD1 levels at four and ten weeks post-surgery. Additionally, lean mice displayed significantly lowered mRNA levels of 11β-HSD1 in subcutaneo
Akalestou E, Suba K, Lopez-Noriega L, et al., 2020, Intravital imaging of islet Ca<sup>2+</sup> 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, Lopez-Noriega L, Leclerc I, et al., 2019, Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Bariatric surgery has been established to improve insulin sensitivity and glucose clearance, but also increases insulin and glucagon secretion. Each of the above effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To determine whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Eighteen lean mice underwent VSG (n=8) or sham (n=9) surgery. Glucose tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if pharmacological SGLT2 inhibition has the same euglycemic effects after bariatric surgery. Kidneys were harvested from fed mice and SGLT2 expression was analysed using Quantitative reverse-transcription PCR and immunofluorescence.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>VSG mice displayed significantly improved glucose tolerance (AUC=103±6.8; AUC=66.6±2.9 in control and VSG mice, respectively; p<0.001), despite an absence of significant weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). Treatment of sham-operated mice with dapagliflozin (10 mg/kg) improved glucose tolerance. In contrast, dapagliflozin did not further improve glucose tolerance in VSG-operated mice. Moreover, qRT-PCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the mRNA (n=7, p<0.0001) and protein (n=5, p=0.0007) levels four weeks after VSG.</jats:p></jats:sec><jats:sec>&l
McGrath TM, Spreckley E, Rodriguez AF, et al., 2019, The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents
<jats:title>Abstract</jats:title><jats:p>Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of PYY<jats:sub>3-36</jats:sub>, lithium chloride, GLP-1 and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated not mimic satiety. In the<jats:italic>ad libitum</jats:italic>fed state during the light period, meal initiation is governed by complete stomach emptying, whereas in all other conditions there is a graduated response. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake, and how this might be overcome.<jats:italic>In silico</jats:italic>experiments suggest that introducing a minimum intermeal interval or modulating gastric emptying can be as effective as anorectic drug administration.</jats:p>
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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