scholarly journals Glucose homeostasis is impaired in mice deficient in the neuropeptide 26RFa (QRFP)

2020 ◽  
Vol 8 (1) ◽  
pp. e000942
Author(s):  
Mouna El-Mehdi ◽  
Saloua Takhlidjt ◽  
Fayrouz Khiar ◽  
Gaëtan Prévost ◽  
Jean-Luc do Rego ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
Gene Knockout ◽  
Hepatic Glucose Production ◽  
Biologically Active ◽  
Mutant Mice ◽  
Insulin Production ◽  
Coding Region ◽  
The Impact

Introduction26RFa (pyroglutamyl RFamide peptide (QRFP)) is a biologically active peptide that has been found to control feeding behavior by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibited an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. Two-dimensional and three-dimensional immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa−/− mice as compared with the wild-type littermates.ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis, with in particular a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.

scholarly journals Glucose homeostasis is impaired in mice deficient for the neuropeptide 26RFa (QRFP)

2019 ◽  
Author(s):  
Mouna El Mehdi ◽  
Saloua Takhlidjt ◽  
Fayrouz Khiar ◽  
Gaëtan Prévost ◽  
Jean-Luc do Rego ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
Biologically Active ◽  
Mutant Mice ◽  
Insulin Production ◽  
Active Peptide ◽  
Important Regulator ◽  
Biologically Active Peptide ◽  
The Impact

AbstractIntroduction26RFa (QRFP) is a biologically active peptide that has been found to control feeding behaviour by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro-26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibit an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. 2D and 3D immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa-/- mice as compared to the wild-type littermates.ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.Significance of this studyWhat is already known about this subject?26RFa is a biologically active peptide produced in abundance in the gut and the pancreas. 26RFa has been found to regulate glucose homeostasis by acting as an incretin and by increasing insulin sensitivity.What are the new findings?Disruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets, assessing therefore the notion that 26RFa is an important regulator of glucose homeostasis.How might these results change the focus of research or clinical practice?Identification of a novel actor in the regulation of glucose homeostasis is crucial to better understand the general control of glucose metabolism in physiological and pathophysiological conditions, and opens new fields of investigation to develop innovative drugs to treat diabetes mellitus.

Insulin production and glucose metabolism in isolated pancreatic islets of rats with NIDDM

Diabetes ◽  
1988 ◽  
Vol 37 (9) ◽  
pp. 1226-1233 ◽  
Author(s):  
B. Portha ◽  
M. H. Giroix ◽  
P. Serradas ◽  
N. Welsh ◽  
C. Hellerstrom ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Insulin Production ◽  
Isolated Pancreatic Islets

Insulin Production and Glucose Metabolism in Isolated Pancreatic Islets of Rats With NIDDM

Diabetes ◽  
1988 ◽  
Vol 37 (9) ◽  
pp. 1226-1233 ◽  
Author(s):  
B. Portha ◽  
M.-H. Giroix ◽  
P. Serradas ◽  
N. Welsh ◽  
C. Hellerstrom ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Insulin Production ◽  
Isolated Pancreatic Islets

Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice

2021 ◽  
Author(s):  
Yuika Osada ◽  
Shunsaku Nakagawa ◽  
Kanako Ishibe ◽  
Shota Takao ◽  
Aimi Shimazaki ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Kidney Injury ◽  
Short Chain Fatty Acids ◽  
Glucose Levels ◽  
The Impact

Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that the bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. The mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, the renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion (IR). Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to IR injury.

scholarly journals Alteration of Glucose Homeostasis in V1a Vasopressin Receptor-Deficient Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (5) ◽  
pp. 2075-2084 ◽  
Author(s):  
Toshinori Aoyagi ◽  
Jun-ichi Birumachi ◽  
Masami Hiroyama ◽  
Yoko Fujiwara ◽  
Atsushi Sanbe ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Plasma Volume ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Mutant Mice ◽  
Calorie Intake ◽  
Vasopressin Receptor ◽  
V1a Receptor ◽  
Hepatic Glucose

Arginine-vasopressin (AVP) is known to be involved in maintaining glucose homeostasis, and AVP-resistance is observed in poorly controlled non-insulin-dependent diabetes mellitus subjects, resulting in a lowered plasma volume. Recently we reported that V1a vasopressin receptor-deficient (V1aR−/−) mice exhibited a decreased circulating blood volume and hypermetabolism of fat accompanied with impaired insulin-signaling. Here we further investigated the roles of the AVP/V1a receptor in regulating glucose homeostasis and plasma volume using V1aR−/− mice. The plasma glucose levels at the baseline or during a glucose tolerance test were higher in V1aR−/− than wild-type (WT) mice. Moreover, a hyperinsulinemic-euglycemic clamp revealed that the glucose infusion rate was significantly lower in V1aR−/− mice than in WT mice and that hepatic glucose production was higher in V1aR−/− mice than WT mice. In contrast to the increased hepatic glucose production, the liver glycogen content was decreased in the mutant mice. These results indicated that the mutant mice had impaired glucose tolerance. Furthermore, feeding V1aR−/− mice a high-fat diet accompanied by increased calorie intake resulted in significantly overt obesity in comparison with WT mice. In addition, we found that the circulating plasma volume and aldosterone level were decreased in V1aR−/− mice, although the plasma AVP level was increased. These results suggested that the effect of AVP on water recruitment was disturbed in V1aR−/− mice. Thus, we demonstrated that one of the AVP-resistance conditions resulting from deficiency of the V1a receptor leads to decreased plasma volume as well as impaired glucose homeostasis, which can progress to obesity under conditions of increased calorie intake.

scholarly journals A267 ROLE OF INTESTINAL EPITHELIAL NUCLEAR RECEPTOR HNF4A DURING METABOLIC DISORDERS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 144-145
Author(s):  
S Tremblay ◽  
R Girard ◽  
C Noll ◽  
A Carpentier ◽  
F Boudreau
Keyword(s):  
Glucose Metabolism ◽  
Nuclear Receptor ◽  
Intestinal Epithelium ◽  
Mutant Mice ◽  
Mouse Serum ◽  
Intestinal Epithelial ◽  
Metabolic Resistance ◽  
Brown Adipose ◽  
The Impact ◽  
Female Mutant

Abstract Background HNF4α belongs to the hormone nuclear receptor family and is expressed in liver, intestinal epithelium and pancreas where it regulates genes involved in the control of metabolism. Inactivating mutations in the HNF4A gene cause several forms of maturity-onset diabetes of the young (MODY). However, the specific deletion of Hnf4a in mouse pancreatic beta cells does not lead to diabetes, suggesting the contribution of other tissues, such as the intestine, are necessary for the progression of the disease. Aims Our main hypothesis was that intestinal epithelial HNF4α regulates gene products that act through a paracrine mode of communication in the context of glucose metabolism. The aims of this study were to investigate the impact of deleting Hnf4a in the mouse intestinal epithelium during glucose homeostasis and to identify molecular mechanisms involved during glucose-induced obesity resistance. Methods The Villin-Cre recombinase transgenic mouse model was used to conditionally delete Hnf4a in the intestinal epithelium (Hnf4adeltaIEC). Hnf4adeltaIEC mice were put on a high sugar diet for 8 to 12 weeks, using a 30% sucrose supplemented ab lithium water. Blood glucose values in controls and mutants were measured from whole venous blood from fasted mice or during glucose and insulin tolerance tests. Mouse serum hormone levels (Ghrelin, Fibroblast-growth factor-15 (Fgf15), Insulin, Cholecystokinin (CCK), etc.) were measured using mouse ELISA kits. The Promethion High-Definition Room Calorimetry System was used for indirect calorimetry and metabolic studies. Results Both male and female Hnf4adeltaIEC mice displayed a metabolic resistance to develop obesity under sucrose supplementation when compared to control mice. While male mutant mice showed a resistance to obesity after only 2 weeks of treatment, female mutant mice took at least 6 weeks to display some resistance. The gut hormones ghrelin and Fgf15 were also found modified in fasted mutant mice. Female mutant mice presented a significant increase of 1.8 fold in circulating Fgf15 and an increase of 1.4 fold in circulating ghrelin. Similar changes were observed in male mutant mice. However, only male mutant mice presented an insulin resistance and an oral glucose tolerance after between 6 and 8 weeks. Brown adipose tissue (BAT) whitening was observed after 8 weeks of sucrose treatment in control obese animals, a condition that was prevented in Hnf4adeltaIEC mice. Conclusions The identification of paracrine intestinal targets for HNF4α in association with glucose metabolism will provide a better understanding of the molecular nature of tissues crosstalk in energy balance and in metabolism disorders including diabetes and obesity. Funding Agencies CIHR

scholarly journals Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

2021 ◽  
Author(s):  
Mouna El Mehdi ◽  
Saloua Takhlidjt ◽  
Mélodie Devère ◽  
Arnaud Arabo ◽  
Marie-Anne Le Solliec ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Inhibitory Effect ◽  
Neuronal Population ◽  
Biologically Active ◽  
Hypothalamic Nucleus ◽  
Hypothalamic Area ◽  
Antihyperglycemic Effect ◽  
Hypothalamic Regulation

26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

scholarly journals Maternal adaptations of pancreatic islets and glucose metabolism after lactation

2021 ◽  
Vol 248 (1) ◽  
pp. 1-15
Author(s):  
Gustavo Canul-Medina ◽  
Leticia Riverón-Negrete ◽  
Karina Pastén-Hidalgo ◽  
Paulina Morales-Castillo ◽  
Francisco García-Vázquez ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Glucose Homeostasis ◽  
Bone Mineralization ◽  
Undercarboxylated Osteocalcin ◽  
Hormonal Changes ◽  
Serotonin Content

Pancreatic islets adapt to metabolic requirements and the hormonal milieu by modifying their size and hormone secretions. Maternal glucose demands and hormonal changes occur after weaning, to rapidly re-establish bone mineralization. Minimal information exists about glucose metabolism and pancreatic islets after lactation. This study investigated islet morphology and glucose homeostasis for 14 days after lactation in C57BL/6NHHsd mice. Compared to the day of weaning, rapid increases in the islets’ area and number of beta cells were found from the first day post-lactation, attaining maximum values on the third day post-weaning. These changes were accompanied by modifications in glucose-induced insulin secretion, glucose tolerance and insulin sensitivity. Islet-cell proliferation was already augmented before lactation ceased. Serum undercarboxylated osteocalcin concentrations increased significantly post-lactation; however, it is unlikely that this enhancement participates in earlier cell proliferation augmentation or in decreasing insulin sensitivity. Islet serotonin content was barely expressed, and serum calcium concentrations decreased. By the 14th day post-weaning, islets’ area and glucose homeostasis returned to age-matched virgin mice levels. These findings recognize for the first time that increases in islet area and insulin secretion occur during physiological post-weaning conditions. These results open up new opportunities to identify molecules and mechanisms participating in these processes, which will help in developing strategies to combat diabetes.

scholarly journals Long-term disruption of maternal glucose homeostasis induced by prenatal glucocorticoid treatment correlates with miR-29 upregulation

2014 ◽  
Vol 306 (1) ◽  
pp. E109-E120 ◽  
Author(s):  
Patrícia R. Gomes ◽  
Maria F. Graciano ◽  
Lucas C. Pantaleão ◽  
André L. Rennó ◽  
Sandra C. Rodrigues ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucose Intolerance ◽  
Glucose Homeostasis ◽  
Cell Function ◽  
Glucocorticoid Treatment ◽  
Altered Expression ◽  
Maternal Metabolism ◽  
The Impact

Excess of glucocorticoids (GCs) during pregnancy is strongly associated with the programming of glucose intolerance in the offspring. However, the impact of high GC levels on maternal metabolism is not clearly documented. This study aimed to test the hypothesis that mothers exposed to elevated levels of GCs might also display long-term disturbances in glucose homeostasis. Dexamethasone (DEX) was administered noninvasively to the mothers via drinking water between the 14th and the 19th days of pregnancy. Mothers were subjected to glucose and insulin tolerance tests at 1, 2, 3, 6, and 12 mo postweaning. Pregnant rats not treated with DEX and age-matched virgin rats were used as controls. Pancreatic islets were isolated at the 20th day of pregnancy and 12 mo postweaning in order to evaluate glucose-stimulated insulin secretion. The expression of the miR-29 family was also studied due to its responsiveness to GCs and its well-documented role in the regulation of pancreatic β-cell function. Rats treated with DEX during pregnancy presented long-term glucose intolerance and impaired insulin secretion. These changes correlated with 1) increased expression of miR-29 and its regulator p53, 2) reduced expression of syntaxin-1a, a direct target of miR-29, and 3) altered expression of genes related to cellular senescence. Our data demonstrate that the use of DEX during pregnancy results in deleterious outcomes to the maternal metabolism, hallmarked by reduced insulin secretion and glucose intolerance. This maternal metabolic programming might be a consequence of time-sustained upregulation of miR-29s in maternal pancreatic islets.

scholarly journals A transgenic mutant mouse line accompanied by the complete deletion of interleukin-33 showed insulin and leptin resistances

2018 ◽  
Author(s):  
Taku Watanabe ◽  
Tomonori Takeuchi ◽  
Naoto Kubota ◽  
Tasuku Wainai ◽  
Keisuke Kataoka ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Energy Homeostasis ◽  
Hepatic Glucose Production ◽  
Mutant Mice ◽  
Obesity And Diabetes ◽  
Homozygous Mutant ◽  
Complete Deletion

ABSTRACTInterleukin (IL) −33 has been identified as a member of the IL-1 family. Members of the IL-1 family have been reported to be involved in the regulation of energy homeostasis and glucose metabolism. Homozygous transgenic mutant mice of FLP14 line, that we previously generated, unexpectedly developed mature-onset obesity and diabetes. Through genetic investigations, we found that insertion of the transgenes had resulted in complete deletion of the Il33 gene. These obese male homozygous mutant mice exhibited hyperphagia with hyperleptinemia and insulin resistance caused by increased hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. As a result of examining preobese male homozygous mutant mice to investigate with the exclusion of the effect of obesity, hyperphagia with hyperleptinemina and insulin resistance caused by decreased glucose uptake in skeletal muscle were already observed, but the increased hepatic glucose production was not. To investigate whether the insulin resistance was caused by deletion of the Il33 gene, we treated these preobese homozygous mutant mice with recombinant IL-33 protein and noted a significant improvement in insulin resistance. Thus, insulin resistance in these homozygous mutant mice was caused, at least in part, by IL-33 deficiency, suggesting a favorable role of IL-33 for glucose metabolism in the skeletal muscle.

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