scholarly journals Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice

2015 ◽  
Vol 39 (6) ◽  
pp. 949-958 ◽  
Author(s):  
L Yuan ◽  
X Luo ◽  
M Zeng ◽  
Y Zhang ◽  
M Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Pi3 Kinase ◽  
Dependent Manner

Glucose homeostasis in rainbow trout fed a high-carbohydrate diet: metformin and insulin interact in a tissue-dependent manner

2011 ◽  
Vol 300 (1) ◽  
pp. R166-R174 ◽  
Author(s):  
S. Polakof ◽  
T. W. Moon ◽  
P. Aguirre ◽  
S. Skiba-Cassy ◽  
S. Panserat
Keyword(s):  
Skeletal Muscle ◽  
Rainbow Trout ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Combined Treatment ◽  
Hypoglycemic Agents ◽  
Dependent Manner ◽  
Metformin Treatment ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Glucose Output

Carnivorous fish species such as the rainbow trout ( Oncorhynchus mykiss ) are considered to be “glucose intolerant” because of the prolonged hyperglycemia experienced after intake of a carbohydrate-enriched meal. In the present study, we use this species to study glucose homeostasis in fish chronically infused with the hypoglycemic agents, insulin, and metformin, and fed with a high proportion of carbohydrates (30%). We analyzed liver, skeletal muscle, and white adipose tissue (WAT), which are insulin- and metformin-specific targets at both the biochemical and molecular levels. Trout infused with the combination of insulin and metformin can effectively utilize dietary glucose at the liver, resulting in lowered glycemia, increased insulin sensitivity, and glucose storage capacity, combined with reduced glucose output. However, in both WAT and skeletal muscle, we observed decreased insulin sensitivity with the combined insulin + metformin treatment, resulting in the absence of changes at the metabolic level in the skeletal muscle and an increased potential for glucose uptake and storage in the WAT. Thus, the poor utilization by rainbow trout of a diet with a high proportion of carbohydrate can at least be partially improved by a combined treatment with insulin and metformin, and the glucose intolerance observed in this species could be, in part, due to some of the downstream components of the insulin and metformin signaling pathways. However, the predominant effects of metformin treatment on the action of insulin in these three tissues thought to be involved in glucose homeostasis remain exclusive in this species.

scholarly journals Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

2020 ◽  
Author(s):  
Marine L. Croze ◽  
Arthur Guillaume ◽  
Mélanie Ethier ◽  
Grace Fergusson ◽  
Caroline Tremblay ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Free Fatty Acid ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Dependent Manner ◽  
High Fat ◽  
Normal Chow ◽  
Free Fatty Acid Receptors

ABSTRACTThe free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

scholarly journals Metformin Targets Foxo1 to Control Glucose Homeostasis

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 873
Author(s):  
Xiaoqin Guo ◽  
Xiaopeng Li ◽  
Wanbao Yang ◽  
Wang Liao ◽  
James Zheng Shen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Glucose Lowering Effect

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.

Caffeine ingestion impairs insulin sensitivity in a dose-dependent manner in both men and women

2013 ◽  
Vol 38 (2) ◽  
pp. 140-147 ◽  
Author(s):  
Marie-Soleil Beaudoin ◽  
Brian Allen ◽  
Gillian Mazzetti ◽  
Peter J. Sullivan ◽  
Terry E. Graham
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Response ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Dependent Manner ◽  
Caffeine Ingestion ◽  
Men And Women ◽  
C Peptide ◽  
Dose Dependent

The effects of alkaloid caffeine on insulin sensitivity have been investigated primarily in men, and with a single caffeine dose most commonly of 5–6 mg·kg−1 of body weight (BW). It is unknown if the effects of caffeine on glucose homeostasis are sex-specific and (or) dose-dependent. This study examined whether caffeine ingestion would disrupt glucose homeostasis in a dose-dependent or threshold manner. It also examined whether sex-specific responses to caffeine exist. It was hypothesized that women would have an exaggerated response to caffeine, and that caffeine would only impair glucose metabolism once a threshold was reached. Twenty-four healthy volunteers (12 males, 12 females) participated in 4 trials, in a crossover, randomized, and double-blind fashion. They ingested caffeine (1, 3, or 5 mg·kg−1 of BW) or placebo followed, 1 h later, by a 2-h oral glucose tolerance test. Glucose, insulin, C-peptide area under the curve (AUC), and insulin sensitivity index data were fitted to a segmented linear model to determine dose–responses. There were no differences between sexes for any endpoints. Regression slopes were significantly different from zero (p < 0.05) for glucose, insulin, and C-peptide AUCs, with thresholds being no different from zero. Increasing caffeine consumption by 1 mg·kg−1 of BW increased insulin and C-peptide AUCs by 5.8% and 8.7%, respectively. Despite this exaggerated insulin response, glucose AUC increased by 11.2 mmol per 120 min·L–1 for each mg·kg−1 BW consumed. These results showed that caffeine ingestion disrupted insulin sensitivity in a dose-dependent fashion beginning at very low doses (0–1 mg·kg−1 BW) in both healthy men and women.

Selective activation of PPARγ in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance

2010 ◽  
Vol 298 (1) ◽  
pp. E28-E37 ◽  
Author(s):  
Rajesh H. Amin ◽  
Suresh T. Mathews ◽  
Heidi S. Camp ◽  
Liyun Ding ◽  
Todd Leff
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Muscle Tissue ◽  
Glucose Homeostasis ◽  
Muscle Cells ◽  
Whole Body ◽  
Fiber Types ◽  
Dependent Manner

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ plays a key role in regulating whole body glucose homeostasis and insulin sensitivity. Although it is expressed most highly in adipose, it is also present at lower levels in many tissues, including skeletal muscle. The role muscle PPARγ plays in metabolic regulation and in mediating the antidiabetic effects of the thiazolidinediones is not understood. The goal of this work was to examine the molecular and physiological effects of PPARγ activation in muscle cells. We found that pharmacological activation of PPARγ in primary cultured myocytes, and genetic activation of muscle PPARγ in muscle tissue of transgenic mice, induced the production of adiponectin directly from muscle cells. This muscle-produced adiponectin was functional and capable of stimulating adiponectin signaling in myocytes. In addition, elevated skeletal muscle PPARγ activity in transgenic mice provided a significant protection from high-fat diet-induced insulin resistance and associated changes in muscle phenotype, including reduced myocyte lipid content and an increase in the proportion of oxidative muscle fiber types. Our findings demonstrate that PPARγ activation in skeletal muscle can have a significant protective effect on whole body glucose homeostasis and insulin resistance and that myocytes can produce and secrete functional adiponectin in a PPARγ-dependent manner. We propose that activation of PPARγ in myocytes induces a local production of adiponectin that acts on muscle tissue to improve insulin sensitivity.

scholarly journals Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Marine L Croze ◽  
Arthur Guillaume ◽  
Mélanie Ethier ◽  
Grace Fergusson ◽  
Caroline Tremblay ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Free Fatty Acid ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Dependent Manner ◽  
High Fat ◽  
Normal Chow ◽  
Free Fatty Acid Receptors

Abstract The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

scholarly journals Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

1995 ◽  
Vol 15 (6) ◽  
pp. 3147-3153 ◽  
Author(s):  
G A Blobel ◽  
C A Sieff ◽  
S H Orkin
Keyword(s):  
Bone Marrow ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Erythroid Cell ◽  
High Dose ◽  
Dependent Manner ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.

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