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Jens J. Holst - One of the best experts on this subject based on the ideXlab platform.
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The liver–Alpha Cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels
Diabetologia, 2021Co-Authors: Christina Gar, Stefanie J. Haschka, Stefanie Kern-matschilles, Barbara Rauch, Vanessa Sacco, Cornelia Prehn, Jerzy Adamski, Jochen Seissler, Nicolai J. Wewer Albrechtsen, Jens J. HolstAbstract:Aims/hypothesis Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–Alpha Cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the Alpha Cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–Alpha Cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% ( n = 39) or >0.5% ( n = 40). Results The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort ( ρ = 0.484, p
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Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes
Diabetologia, 2016Co-Authors: Vivi R. Steenberg, Jens Pedersen, Signe M. Jensen, Andreas N. Madsen, Johanne A. Windeløv, Birgitte Holst, Bjørn Quistorff, Steen S. Poulsen, Jens J. HolstAbstract:Aims/hypothesis Normal glucose metabolism depends on pancreatic secretion of insulin and glucagon. The bihormonal hypothesis states that while lack of insulin leads to glucose underutilisation, glucagon excess is the principal factor in diabetic glucose overproduction. A recent study reported that streptozotocin-treated glucagon receptor knockout mice have normal glucose tolerance. We investigated the impact of acute disruption of glucagon secretin or action in a mouse model of severe diabetes by three different approaches: (1) Alpha Cell elimination; (2) glucagon immunoneutralisation; and (3) glucagon receptor antagonism, in order to evaluate the effect of these on glucose tolerance. Methods Severe diabetes was induced in transgenic and wild-type mice by streptozotocin. Glucose metabolism was investigated using OGTT in transgenic mice with the human diphtheria toxin receptor expressed in proglucagon producing Cells allowing for diphtheria toxin (DT)-induced Alpha Cell ablation and in mice treated with either a specific high affinity glucagon antibody or a specific glucagon receptor antagonist. Results Near-total Alpha Cell elimination was induced in transgenic mice upon DT administration and resulted in a massive decrease in pancreatic glucagon content. Oral glucose tolerance in diabetic mice was neither affected by glucagon immunoneutralisation, glucagon receptor antagonism, nor Alpha Cell removal, but did not deteriorate further compared with mice with intact Alpha Cell mass. Conclusions/interpretation Disruption of glucagon action/secretion did not improve glucose tolerance in diabetic mice. Near-total Alpha Cell elimination may have prevented further deterioration. Our findings support insulin lack as the major factor underlying hyperglycaemia in beta Cell-deficient diabetes.
Qingping Feng - One of the best experts on this subject based on the ideXlab platform.
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Paracrine GABA and insulin regulate pancreatic Alpha Cell proliferation in a mouse model of type 1 diabetes.
Diabetologia, 2017Co-Authors: Allen L. Feng, Yun-yan Xiang, Le Gui, Gesthika Kaltsidis, Qingping FengAbstract:This study aimed to elucidate the mechanism of increased proliferation of Alpha Cells in recent-onset type 1 diabetes. Pancreatic beta Cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits Alpha Cell secretion of glucagon. We explored the roles of GABA in Alpha Cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro. Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10 mg/kg daily) for 12 days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2 days. The effects of GABA treatment on STZ-induced Alpha Cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 Cell proliferation was also examined. STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta Cells 12 h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the Alpha Cells at day 1, and a significant increase in Alpha Cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta Cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive Cells, Alpha Cell mass and hyperglucagonaemia. STZ treatment also increased Alpha Cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca2+ and p-mTOR, and decreased the proliferation rate of αTC1-6 Cells. GABA signalling critically controls the Alpha Cell population in pancreatic islets. Low intraislet GABA may contribute to Alpha Cell hyperplasia in early type 1 diabetes.
Ivan Quesada - One of the best experts on this subject based on the ideXlab platform.
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Morphological and functional adaptations of pancreatic Alpha-Cells during late pregnancy in the mouse
Metabolism: clinical and experimental, 2019Co-Authors: Cristina Quesada-candela, Paloma Alonso-magdalena, Laura Marroquí, Ivan Quesada, Eva Tudurí, Angel NadalAbstract:Abstract Background Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-Cell to maintain normoglycemia. However, although pancreatic Alpha-Cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy. Material and methods Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.5 (G18.5) and their isolated pancreatic islets were used for in vivo and ex vivo studies, respectively. The effect of pregnancy hormones was tested in glucagon-secreting α-TC1.9 Cells. Immunohistochemical analysis was performed in pancreatic slices. Glucagon gene expression was monitored by RT-qPCR. Glucagon secretion and plasma hormones were measured by ELISA. Results Pregnant mice on G18.5 exhibited Alpha-Cell hypertrophy as well as augmented Alpha-Cell area and mass. This Alpha-Cell mass expansion was mainly due to increased proliferation. No changes in Alpha-Cell apoptosis, ductal neogenesis, or Alpha-to-beta transdifferentiation were found compared with controls. Pregnant mice on G18.5 exhibited hypoglucagonemia. Additionally, in vitro glucagon secretion at low glucose levels was decreased in isolated islets from pregnant animals. Glucagon content was also reduced. Experiments in α-TC1.9 Cells indicated that, unlike estradiol and progesterone, placental lactogens and prolactin stimulated Alpha-Cell proliferation. Placental lactogens, prolactin and estradiol also inhibited glucagon release from α-TC1.9 Cells at low glucose levels. Conclusions The pancreatic Alpha-Cell in mice undergoes several morphofunctional changes during late pregnancy, which may contribute to proper glucose homeostasis. Gestational hormones are likely involved in these processes.
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Pancreatic Alpha-Cell mass in the early-onset and advanced stage of a mouse model of experimental autoimmune diabetes.
Scientific reports, 2019Co-Authors: Eva Bru-tari, Nadia Cobo-vuilleumier, Paloma Alonso-magdalena, Reinaldo S. Dos Santos, Laura Marroquí, Angel Nadal, Benoit R. Gauthier, Ivan QuesadaAbstract:Most studies in type 1 diabetes (T1D) have focused on the loss of the pancreatic beta-Cell population. However, despite the involvement of the Alpha-Cell in the aetiology and complications of T1D, little is known about the regulation of the pancreatic Alpha-Cell mass in this disease. The need for a better understanding of this process is further emphasized by recent findings suggesting that Alpha-Cells may constitute a potential reservoir for beta-Cell regeneration. In this study, we characterized the pancreatic Alpha-Cell mass and its regulatory processes in the transgenic RIP-B7.1 mice model of experimental autoimmune diabetes (EAD). Diabetic mice presented insulitis, hyperglycaemia, hypoinsulinemia and hyperglucagonemia along with lower pancreatic insulin content. While Alpha-Cell mass and pancreatic glucagon content were preserved at the early-onset of EAD, both parameters were reduced in the advanced phase. At both stages, Alpha-Cell size, proliferation and ductal neogenesis were up-regulated, whereas apoptosis was almost negligible. Interestingly, we found an increase in the proportion of glucagon-containing Cells positive for insulin or the beta-Cell transcription factor PDX1. Our findings suggest that pancreatic Alpha-Cell renewal mechanisms are boosted during the natural course of EAD, possibly as an attempt to maintain the Alpha-Cell population and/or to increase beta-Cell regeneration via Alpha-Cell transdifferentiation.
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Pancreatic Alpha-Cells from female mice undergo morphofunctional changes during compensatory adaptations of the endocrine pancreas to diet-induced obesity
Scientific reports, 2015Co-Authors: Beatriz Merino, Paloma Alonso-magdalena, Laura Marroquí, Angel Nadal, Mónica Lluesma, Patricia Ñeco, Alejandro González, Marta García-arévalo, Ivan QuesadaAbstract:Obesity is frequently associated with insulin resistance. To compensate for this situation and maintain normoglycaemia, pancreatic beta-Cells undergo several morphofunctional adaptations, which result in insulin hypersecretion and hyperinsulinaemia. However, no information exists about pancreatic Alpha-Cells during this compensatory stage of obesity. Here, we studied Alpha-Cells in mice fed a high-fat diet (HFD) for 12 weeks. These animals exhibited hyperinsulinaemia and normoglycaemia compared with control animals in addition to hypoglucagonaemia. While the in vivo response of glucagon to hypoglycaemia was preserved in the obese mice, the suppression of glucagon secretion during hyperglycaemia was impaired. Additionally, in vitro glucagon release at low glucose levels and glucagon content in isolated islets were decreased, while Alpha-Cell exocytosis remained unchanged. Assessment of morphological parameters revealed that Alpha-Cell area was reduced in the pancreas of the obese mice in association with Alpha-Cell hypotrophy, increased apoptosis and decreased proliferation. HFD feeding for 24 weeks led to significant deterioration in beta-Cell function and glucose homeostasis. Under these conditions, the majority of Alpha-Cell changes were reversed and became comparable to controls. These findings indicate that pancreatic compensatory adaptations during obesity may also involve pancreatic Alpha-Cells. Additionally, defects in Alpha-Cell function during obesity may be implicated in progression to diabetes.
Cornelia Prehn - One of the best experts on this subject based on the ideXlab platform.
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The liver–Alpha Cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels
Diabetologia, 2021Co-Authors: Christina Gar, Stefanie J. Haschka, Stefanie Kern-matschilles, Barbara Rauch, Vanessa Sacco, Cornelia Prehn, Jerzy Adamski, Jochen Seissler, Nicolai J. Wewer Albrechtsen, Jens J. HolstAbstract:Aims/hypothesis Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–Alpha Cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the Alpha Cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–Alpha Cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% ( n = 39) or >0.5% ( n = 40). Results The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort ( ρ = 0.484, p
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disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver Alpha Cell axis
American Journal of Physiology-endocrinology and Metabolism, 2018Co-Authors: Katrine D. Galsgaard, Cornelia Prehn, Jerzy Adamski, Marie Winthersorensen, Cathrine Orskov, Hannelouise Kissow, Steen Seier Poulsen, Hendrik Vilstrup, Sara L Jepsen, Bolette HartmannAbstract:Glucagon secreted from the pancreatic Alpha-Cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolis...
Jerzy Adamski - One of the best experts on this subject based on the ideXlab platform.
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The liver–Alpha Cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels
Diabetologia, 2021Co-Authors: Christina Gar, Stefanie J. Haschka, Stefanie Kern-matschilles, Barbara Rauch, Vanessa Sacco, Cornelia Prehn, Jerzy Adamski, Jochen Seissler, Nicolai J. Wewer Albrechtsen, Jens J. HolstAbstract:Aims/hypothesis Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–Alpha Cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the Alpha Cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–Alpha Cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% ( n = 39) or >0.5% ( n = 40). Results The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort ( ρ = 0.484, p
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disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver Alpha Cell axis
American Journal of Physiology-endocrinology and Metabolism, 2018Co-Authors: Katrine D. Galsgaard, Cornelia Prehn, Jerzy Adamski, Marie Winthersorensen, Cathrine Orskov, Hannelouise Kissow, Steen Seier Poulsen, Hendrik Vilstrup, Sara L Jepsen, Bolette HartmannAbstract:Glucagon secreted from the pancreatic Alpha-Cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolis...