scholarly journals Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

2014 ◽  
Vol 27 (1) ◽  
pp. 48-62 ◽  
Author(s):  
Laura Marroquí ◽  
Paloma Alonso-Magdalena ◽  
Beatriz Merino ◽  
Esther Fuentes ◽  
Angel Nadal ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Diabetic Patients ◽  
Β Cells ◽  
Glucagon Receptor ◽  
Nutrient Regulation ◽  
New Information ◽  
Experimental Approaches ◽  
Glucagon And Insulin

Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic α- and β-cells, respectively. While β-cells have been the focus of intense research, less is known about α-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of α-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and α-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in α-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

scholarly journals δ-Cells: The Neighborhood Watch in the Islet Community

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 74
Author(s):  
Rui Gao ◽  
Tao Yang ◽  
Quan Zhang
Keyword(s):  
Cell Function ◽  
Glucagon Secretion ◽  
Β Cells ◽  
Interactive Communication ◽  
Neighborhood Watch ◽  
Insulin And Glucagon Secretion ◽  
Urocortin 3 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucagon And Insulin

Somatostatin-secreting δ-cells have aroused great attention due to their powerful roles in coordination of islet insulin and glucagon secretion and maintenance of glucose homeostasis. δ-cells exhibit neuron-like morphology with projections which enable pan-islet somatostatin paracrine regulation despite their scarcity in the islets. The expression of a range of hormone and neurotransmitter receptors allows δ-cells to integrate paracrine, endocrine, neural and nutritional inputs, and provide rapid and precise feedback modulations on glucagon and insulin secretion from α- and β-cells, respectively. Interestingly, the paracrine tone of δ-cells can be effectively modified in response to factors released by neighboring cells in this interactive communication, such as insulin, urocortin 3 and γ-aminobutyric acid from β-cells, glucagon, glutamate and glucagon-like peptide-1 from α-cells. In the setting of diabetes, defects in δ-cell function lead to suboptimal insulin and glucagon outputs and lift the glycemic set-point. The interaction of δ-cells and non-δ-cells also becomes defective in diabetes, with reduces paracrine feedback to β-cells to exacerbate hyperglycemia or enhanced inhibition of α-cells, disabling counter-regulation, to cause hypoglycemia. Thus, it is possible to restore/optimize islet function in diabetes targeting somatostatin signaling, which could open novel avenues for the development of effective diabetic treatments.

scholarly journals The RNA-binding protein LARP1 is dispensable for pancreatic β-cell function and mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joao Pedro Werneck-de-Castro ◽  
Flavia Leticia Martins Peçanha ◽  
Diego Henrique Silvestre ◽  
Ernesto Bernal-Mizrachi
Keyword(s):  
Glucose Homeostasis ◽  
Ribosome Biogenesis ◽  
Rna Binding ◽  
Cell Function ◽  
Cell Mass ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Fasting Glycemia ◽  
Mouse Islets

AbstractMechanistic target of rapamycin complex 1 (mTORC1) deficiency or chronic hyperactivation in pancreatic β-cells leads to diabetes. mTORC1 complexes with La-related protein 1 (LARP1) to specifically regulate the expression of 5′ terminal oligopyrimidine tract (5′TOP) mRNAs which encode proteins of the translation machinery and ribosome biogenesis. Here we show that LARP1 is the most expressed LARP in mouse islets and human β-cells, being 2–4-fold more abundant than LARP1B, a member of the family that also interacts with mTORC1. Interestingly, β-cells from diabetic patients have higher LARP1 and LARP1B expression. However, specific deletion of Larp1 gene in β-cells (β-Larp1KO mice) did not impair insulin secretion and glucose metabolism in male and female mice. High fat or high branched-chain amino acid (BCAA) diets did not disturb glucose homeostasis compared to control littermates up to 8 weeks; BCAA diet slightly impaired glucose tolerance in the β-Larp1KO mice at 16 weeks. However, no differences in plasma insulin levels, non-fasting glycemia and β-cell mass were observed in the β-Larp1KO mice. In conclusion, LARP1 is the most abundant LARP in mouse islets and human β-cells, and it is upregulated in diabetic subjects. However, genetically disruption of Larp1 gene did not impact glucose homeostasis in basal and diabetogenic conditions, suggesting no major role for LARP1 in β-cells.

scholarly journals VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Frank Chenfei Ning ◽  
Nina Jensen ◽  
Jiarui Mi ◽  
William Lindström ◽  
Mirela Balan ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Glucose Homeostasis ◽  
Lipid Accumulation ◽  
Cell Function ◽  
Lipid Uptake ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Β Cell Function ◽  
Triglyceride Content

AbstractType 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.

scholarly journals Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

2008 ◽  
Vol 199 (1) ◽  
pp. 5-19 ◽  
Author(s):  
Ivan Quesada ◽  
Eva Tudurí ◽  
Cristina Ripoll ◽  
Ángel Nadal
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Critical Role ◽  
Glucagon Secretion ◽  
Cell Physiology ◽  
Cellular Mechanisms ◽  
Multiple Control ◽  
Hepatic Glucose ◽  
Glucose Synthesis ◽  
Blood Glucose Concentrations

The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of α-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on α-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to α-cell function are also discussed in this review. A better understanding of the α-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.

scholarly journals Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

2020 ◽  
Author(s):  
Ada Admin ◽  
Nadejda Bozadjieva Kramer ◽  
Camila Lubaczeuski ◽  
Manuel Blandino-Rosano ◽  
Grant Barker ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Conditional Deletion ◽  
Mtorc1 Signaling ◽  
Nutrient Signaling ◽  
A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2<sup>KO</sup>). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2<sup>KO</sup> was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2<sup>KO</sup> mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2<sup>KO</sup> mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

scholarly journals Translational factor eIF4G1 regulates glucose homeostasis and pancreatic β-cell function

2020 ◽  
Author(s):  
Ada Admin ◽  
Seokwon Jo ◽  
Amber Lockridge ◽  
Ramkumar Mohan ◽  
Nicholas Esch ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Scaffolding Protein ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Initiation Complex ◽  
Β Cell Function

Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling, is associated with diabetes in both humans and mice. In the present study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells <i>in vivo</i> (βeIF4G1KO). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in both proliferation and apoptosis in β-cells of βeIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca<sup>2+</sup> flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5’-cap binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single β-cells or intact islets of βeIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and β-cell function.

scholarly journals Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia

2020 ◽  
Author(s):  
Nadejda Bozadjieva Kramer ◽  
Camila Lubaczeuski ◽  
Manuel Blandino-Rosano ◽  
Grant Barker ◽  
George K. Gittes ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Glucagon Receptor ◽  
Glucose Levels ◽  
Conditional Deletion ◽  
Mtorc1 Signaling ◽  
Nutrient Signaling ◽  
A Cell

Elevation of glucagon levels and increase in a-cell mass are associated with states of hyperglycemia in diabetes. Our previous studies have highlighted the role of nutrient signaling via mTOR Complex 1 (mTORC1) regulation that controls glucagon secretion and a-cell mass. The current studies investigated the effects of activation of nutrient signaling by conditional deletion of the mTORC1 inhibitor, TSC2, in a-cells (aTSC2<sup>KO</sup>). We showed that activation of mTORC1 signaling is sufficient to induce chronic hyperglucagonemia as a result of a-cell proliferation, cell size and mass expansion. Hyperglucagonemia in aTSC2<sup>KO</sup> was associated with an increase in glucagon content and enhanced glucagon secretion. This model allowed us to identify the effects of chronic hyperglucagonemia on glucose homeostasis by inducing insulin secretion and resistance to glucagon in the liver. Liver glucagon resistance in aTSC2<sup>KO</sup> mice were characterized by reduced expression of the glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and genes involved in amino acid metabolism and urea production. Glucagon resistance in aTSC2<sup>KO</sup> mice was associated with improved glucose levels in Streptozotocin (STZ)-induced β-cell destruction and HFD-induced glucose intolerance. These studies demonstrate that chronic hyperglucagonemia can improve glucose homeostasis by inducing glucagon resistance in the liver.

scholarly journals Impaired glucose tolerance, glucagon, and insulin responses in mice lacking the loop diuretic-sensitive Nkcc2a transporter

2019 ◽  
Vol 317 (4) ◽  
pp. C843-C856 ◽  
Author(s):  
Lisa Kelly ◽  
Mohammed M. Almutairi ◽  
Shams Kursan ◽  
Romario Pacheco ◽  
Eduardo Dias-Junior ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Β Cells ◽  
Islet Size ◽  
Low Levels ◽  
Glucagon And Insulin ◽  
Cell Expression ◽  
Insulin Responses ◽  
Gluconeogenic Substrate

The Na+K+2Cl− cotransporter-2 ( Nkcc2, Slc12a1) is abundantly expressed in the kidney and its inhibition with the loop-diuretics bumetanide and furosemide has been linked to transient or permanent hyperglycemia in mice and humans. Notably, Slc12a1 is expressed at low levels in hypothalamic neurons and in insulin-secreting β-cells of the endocrine pancreas. The present study was designed to determine if global elimination of one of the Slc12a1 products, i.e., Nkcc2 variant a ( Nkcc2a), the main splice version of Nkcc2 found in insulin-secreting β-cells, has an impact on the insulin and glucagon secretory responses and fuel homeostasis in vivo. We have used dynamic tests of glucose homeostasis in wild-type mice and mice lacking both alleles of Nkcc2a ( Nkcc2aKO) and assessed their islet secretory responses in vitro. Under basal conditions, Nkcc2aKO mice have impaired glucose homeostasis characterized by increased blood glucose, intolerance to the sugar, delayed/blunted in vivo insulin and glucagon responses to glucose, and increased glycemic responses to the gluconeogenic substrate alanine. Further, we provide evidence of conserved quantitative secretory responses of Nkcc2aKO islets within a context of increased islet size related to hyperplastic/hypertrophic glucagon- and insulin-positive cells (α-cells and β-cells, respectively), normal total islet Cl− content, and reduced β-cell expression of the Cl− extruder Kcc2.

scholarly journals Effect of Glucagon-Like Peptide-1 on α- and β-Cell Function in C-Peptide-Negative Type 1 Diabetic Patients

2010 ◽  
Vol 24 (4) ◽  
pp. 875-875
Author(s):  
Urd Kielgast ◽  
Meena Asmar ◽  
Sten Madsbad ◽  
Jens J. Holst
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Diabetic Patients ◽  
Β Cell ◽  
C Peptide ◽  
Endogenous Insulin Secretion ◽  
Endogenous Insulin ◽  
Type 1 Diabetic Patients

Abstract Context: The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect. Objective: Our objective was to characterize the α- and β-cell responses to GLP-1 in type 1 diabetic patients without residual β-cell function. Methods: Nine type 1 diabetic patients, classified as C-peptide negative by a glucagon test, were clamped at plasma glucose of 20 mmol/liter for 90 min with arginine infusion at time 45 min and concomitant infusion of GLP-1 (1.2 pmol/kg · min) or saline. Results: Infusion with GLP-1 increased C-peptide concentration just above the detection limit of 33 pmol/liter in one patient, but C-peptide remained immeasurable in all other patients. In the eight remaining patients, total area under the curve of glucagon was significantly decreased with GLP-1 compared with saline: 485 ± 72 vs. 760 ± 97 pmol/liter · min (P &lt; 0.001). In addition, GLP-1 decreased the arginine-stimulated glucagon release (incremental AUC of 103 ± 21 and 137 ± 16 pmol/liter · min, with GLP-1 and saline, respectively, P &lt; 0.05). Conclusions: In type 1 diabetic patients without endogenous insulin secretion, GLP-1 decreases the glucagon secretion as well as the arginine-induced glucagon response during hyperglycemia. GLP-1 induced endogenous insulin secretion in one of nine type 1 diabetic patients previously classified as being without endogenous insulin secretion.

scholarly journals GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells

2021 ◽  
Vol 7 (11) ◽  
pp. eabf1948
Author(s):  
K. El ◽  
S. M. Gray ◽  
M. E. Capozzi ◽  
E. R. Knuth ◽  
E. Jin ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nutrient Intake ◽  
Cell Communication ◽  
Glucagon Secretion ◽  
Optimal Level ◽  
Β Cells ◽  
Β Cell ◽  
Postprandial State ◽  
Glucagon And Insulin

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid–stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in β cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to β cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis.

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