darrenG10
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Our data indicate that GLP‐1 infusion restores the anabolic response to EAA provision in older muscle, which may help explain the increase or maintenance in muscle mass observed in these previous studies.
We show that GLP-1 up-regulated IGF-1R expression by a protein kinase A-dependent translational control mechanism, whereas isobutylmethylxanthine, which led to higher intracellular accumulation of cAMP than GLP-1, increased both IGF-1R transcription and translation. We then demonstrated, using MIN6 cells and primary islets, that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF-2 secretion. We showed that GLP-1-induced primary beta-cell proliferation was suppressed by Igf-1r gene inactivation and by IGF-2 immunoneutralization or knockdown. Together our data show that regulation of beta-cell number and function by GLP-1 depends on the cAMP/protein kinase A mediated-induction of IGF-1R expression and the increased activity of an IGF-2/IGF-1R autocrine loop.
To investigate whether dulaglutide treatment could inhibit the expression of MuRF-1 and atrogin-1 in disuse condition, we examined the mRNA and protein levels of MuRF-1 and atrogin-1 in the GA muscle of dulaglutide-treated mice (ID group). Both mRNA and protein levels of these markers increased in disuse condition (IV group), and dulaglutide treatment (ID group) attenuated the increase in these levels (Figures 3A–C). Myostatin is a negative regulator of skeletal muscle growth and the knockdown of myostatin expression could prevent muscle wasting after 14 days of casting (Murphy et al., 2011). Both myostatin mRNA and protein levels significantly decreased after dulaglutide treatment (Figures 3A–C). Thus, dulaglutide intervention downregulated the expression of myostatin and the proteins involved in protein degradation, thereby contributing to the attenuation of the loss of muscle proteins in disuse condition. We examined the expression of myosin heavy chain (MHC), a motor protein of the muscle filament. Treatment with dulaglutide increased the mRNA level of MHC, including MHC type I, MHC type IIa, and type IIb (Figure 3D) as well as MHC protein expression
GLP-1 receptor agonists have been used to treat diabetes (Arnés et al., 2009). Aside from the blood glucose-lowering effects, GLP-1 receptor agonists also exert beneficial effects on the skeletal muscle by increasing glucose uptake (Thompson and Kanamarlapudi, 2013), fat oxidation, and thermogenic gene expression (Choung et al., 2017). In addition, GLP-1 receptor agonist, Ex-4, imparts therapeutic effects in muscle atrophy induced by dexamethasone (Hong et al., 2019). In the present study, we investigated the effect of dulaglutide, a GLP-1 receptor agonist, on disuse-induced muscle atrophy and evaluated the underlying mechanisms.
As GLP-1 receptor agonists reduce food intake (Ronveaux et al., 2014; Wan et al., 2017), the same amount of food as that consumed by dulaglutide-treated group was provided to the control vehicle-treated group. We examined body weight changes and found that immobilization significantly reduced body weight, and that dulaglutide treatment had no effect on body weight (Figure 1B). Decreased muscle strength is a diagnostic feature of muscle atrophy (Khan et al., 2013). Muscle strength decreased in mice following 10 days of immobilization (Figure 1B), contradicting the results of a previous report (Khan et al., 2013). Dulaglutide treatment showed stronger grip strength in immobilized mice than in vehicle-treated mice and recovered total muscle mass in mice subjected to disuse condition (Figure 1C). In a rodent immobilization model, the loss in extensor muscles of the ankle such as GA muscle was higher than that in the flexor muscles (TA and EDL) (Bodine, 2013). Here, we reported a significant reduction in GA, TA, and QD muscle weights following 10 days of immobilization. In particular, dulaglutide injection significantly increased GA muscle weight; we chose the GA muscle for further investigation. Mean CSA of the muscle decreased upon immobilization as previously reported (Caron et al., 2009; Ito et al., 2017) and dulaglutide treatment restored the CSA. Furthermore, the size of the predominant myofiber was larger in the dulaglutide-treated mice than in the vehicle-treated mice (Figure 2C). These results indicate that dulaglutide attenuated muscle wasting and increased muscle strength in disuse condition.In conclusion, we demonstrate that treatment with dulaglutide, a GLP-1 receptor agonist, could recover muscle strength, muscle mass, and muscle fiber size, which were reduced during immobilization. Dulaglutide treatment attenuated the induction of atrophic genes, such as those encoding MuRF-1, atrogin-1, and myostatin, and enhanced MHC expression. In addition, dulaglutide treatment inhibited the expression of inflammatory cytokines and apoptotic genes through the induction of heat shock protein 72 (Hsp72) expression via AMPK activation, contributing to the amelioration of disuse-induced muscle atrophy.
GLP-1-based therapies downregulate proinflammatory responses in inflammatoryrelated diseases. This review concludes that GLP-1-based therapy has beneficial effects on inflammatory disease. Thus GLP-1, GLP-1Ragonists, and DPP-4 inhibitors might have important roles as mediators of inflammation
glucagon-like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk.analysis of the effects of GLP-1RAs on bone physiology with special focuses on the mode of action including effects on bone quality, blood flow to bone and on the hormonal regulation of bone metabolism.
OCTOBER: To explore the effects of the glucagon-like peptide 1 (GLP-1) liraglutide on the penile erectile function of rats with diabetic erectile dysfunction (DED) by observing the impact of liraglutide on the expression of eNOS in the corpus cavernosum of diabetic rats.
Methods: We randomly divided 30 six-week-old male SD rats into a normal control (n = 10) and an experimental group (n = 20) , established models of diabetes mellitus (DM) in the experimental rats, and subdivided them into a DM (n = 8) and a GLP-1 group (n = 8) to receive intramuscular injection of normal saline and liraglutide at 5 mg per kg of the body weight per day, respectively. After 12 weeks of intervention, we obtained the levels of FPG, FINS, TG, TC, HDL-C, LDL-C, testosterone, and IL-6 and the indexes of Homa-IR and Homa-β, detected the expressions of Akt/p-Akt and eNOS/p-eNOS in the corpus cavernosum by Western blot, and compared the erectile function between different groups.
Results: The frequency and rate of penile erection were significantly lower in the DM group than in the GLP-1 and normal control groups (P < 0.05) and also lower in the GLP-1 group than in the normal controls (P < 0.05). Immunofluorescence staining showed the expression of eNOS mainly in the cytoplasm of the cavernosal vessels and sinusoidal endothelial cells, markedly lower in the DM and GLP-1 groups than in the normal rats (P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05). The level of eNOS/p-eNOS in the penile tissue was significantly decreased in the DM and GLP-1 groups in comparison with the normal controls (P < 0.01 or P < 0.05), while that of p-eNOS was markedly increased in the GLP-1 group as compared with the DM group (P < 0.05). No statistically significant differences were observed in the Akt level among the three groups of animals (P > 0.05). The expression of p-Akt was remarkably reduced in the DM and GLP-1 groups in comparison with the control rats (P < 0.01 or P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05).
Conclusion: GLP-1 can protect the function of endothelial cells in the corpus cavernosum and improve the erectile function of DED rats by regulating the Akt/ eNOS signaling pathway, which indicates that GLP-1 could be an important option for the treatment and prevention of DED.
Insulin and Insulin Growth Factor-1 (IGF-1) play a major role in body homeostasis and glucose regulation. They also have paracrine/autocrine functions in the brain. The Insulin/IGF-1 signaling pathway contributes to the control of neuronal excitability, nerve cell metabolism and cell survival. Glucagon like peptide-1 (GLP-1), known as an insulinotropic hormone has similar functions and growth like properties as insulin/IGF-1. Growing evidence suggests that dysfunction of these pathways contribute to the progressive loss of neurons in Alzheimer's disease (AD) and Parkinson's disease (PD), the two most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting insulin/IGF-1 and GLP-1 signaling with currently available anti-diabetics. These studies have shown that administration of insulin, IGF-1 and GLP-1 agonists reverses signaling abnormalities and has positive effects on surrogate markers of neurodegeneration and behavioral outcomes. Several proof-of-concept studies are underway that attempt to translate the encouraging preclinical results to patients suffering from AD and PD. In the first part of this review, we discuss physiological functions of insulin/IGF-1 and GLP-1 signaling pathways including downstream targets and receptors distribution within the brain. In the second part, we undertake a comprehensive overview of preclinical studies targeting insulin/IGF-1 or GLP-1 signaling for treating AD and PD. We then detail the design of clinical trials that have used anti-diabetics for treating AD and PD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into treatments for patients with AD and PD.
The peptide hormone glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion and inhibits both gastric emptying and glucagon secretion. GLP-1 receptor (GLP-1R) agonists control glycemia via glucose-dependent mechanisms of action and promote weight loss in obese and diabetic individuals. Nevertheless, the mechanisms and cellular targets transducing the weight loss effects remain unclear. Two recent studies in the JCI provide insight into the neurons responsible for this effect. Sisley et al. reveal that GLP-1R agonist-induced weight loss requires GLP-1Rs in the CNS, while Secher et al. reveal that a small peptide GLP-1R agonist penetrates the brain and activates a subset of GLP-1R-expressing neurons in the arcuate nucleus to produce weight loss. Together, these two studies elucidate pathways that inform strategies coupling GLP-1R signaling to control of body weight in patients with diabetes or obesity.
We show that GLP-1 up-regulated IGF-1R expression by a protein kinase A-dependent translational control mechanism, whereas isobutylmethylxanthine, which led to higher intracellular accumulation of cAMP than GLP-1, increased both IGF-1R transcription and translation. We then demonstrated, using MIN6 cells and primary islets, that the glucose competence of these cells was dependent on the level of IGF-1R expression and on IGF-2 secretion. We showed that GLP-1-induced primary beta-cell proliferation was suppressed by Igf-1r gene inactivation and by IGF-2 immunoneutralization or knockdown. Together our data show that regulation of beta-cell number and function by GLP-1 depends on the cAMP/protein kinase A mediated-induction of IGF-1R expression and the increased activity of an IGF-2/IGF-1R autocrine loop.
To investigate whether dulaglutide treatment could inhibit the expression of MuRF-1 and atrogin-1 in disuse condition, we examined the mRNA and protein levels of MuRF-1 and atrogin-1 in the GA muscle of dulaglutide-treated mice (ID group). Both mRNA and protein levels of these markers increased in disuse condition (IV group), and dulaglutide treatment (ID group) attenuated the increase in these levels (Figures 3A–C). Myostatin is a negative regulator of skeletal muscle growth and the knockdown of myostatin expression could prevent muscle wasting after 14 days of casting (Murphy et al., 2011). Both myostatin mRNA and protein levels significantly decreased after dulaglutide treatment (Figures 3A–C). Thus, dulaglutide intervention downregulated the expression of myostatin and the proteins involved in protein degradation, thereby contributing to the attenuation of the loss of muscle proteins in disuse condition. We examined the expression of myosin heavy chain (MHC), a motor protein of the muscle filament. Treatment with dulaglutide increased the mRNA level of MHC, including MHC type I, MHC type IIa, and type IIb (Figure 3D) as well as MHC protein expression
GLP-1 receptor agonists have been used to treat diabetes (Arnés et al., 2009). Aside from the blood glucose-lowering effects, GLP-1 receptor agonists also exert beneficial effects on the skeletal muscle by increasing glucose uptake (Thompson and Kanamarlapudi, 2013), fat oxidation, and thermogenic gene expression (Choung et al., 2017). In addition, GLP-1 receptor agonist, Ex-4, imparts therapeutic effects in muscle atrophy induced by dexamethasone (Hong et al., 2019). In the present study, we investigated the effect of dulaglutide, a GLP-1 receptor agonist, on disuse-induced muscle atrophy and evaluated the underlying mechanisms.
As GLP-1 receptor agonists reduce food intake (Ronveaux et al., 2014; Wan et al., 2017), the same amount of food as that consumed by dulaglutide-treated group was provided to the control vehicle-treated group. We examined body weight changes and found that immobilization significantly reduced body weight, and that dulaglutide treatment had no effect on body weight (Figure 1B). Decreased muscle strength is a diagnostic feature of muscle atrophy (Khan et al., 2013). Muscle strength decreased in mice following 10 days of immobilization (Figure 1B), contradicting the results of a previous report (Khan et al., 2013). Dulaglutide treatment showed stronger grip strength in immobilized mice than in vehicle-treated mice and recovered total muscle mass in mice subjected to disuse condition (Figure 1C). In a rodent immobilization model, the loss in extensor muscles of the ankle such as GA muscle was higher than that in the flexor muscles (TA and EDL) (Bodine, 2013). Here, we reported a significant reduction in GA, TA, and QD muscle weights following 10 days of immobilization. In particular, dulaglutide injection significantly increased GA muscle weight; we chose the GA muscle for further investigation. Mean CSA of the muscle decreased upon immobilization as previously reported (Caron et al., 2009; Ito et al., 2017) and dulaglutide treatment restored the CSA. Furthermore, the size of the predominant myofiber was larger in the dulaglutide-treated mice than in the vehicle-treated mice (Figure 2C). These results indicate that dulaglutide attenuated muscle wasting and increased muscle strength in disuse condition.In conclusion, we demonstrate that treatment with dulaglutide, a GLP-1 receptor agonist, could recover muscle strength, muscle mass, and muscle fiber size, which were reduced during immobilization. Dulaglutide treatment attenuated the induction of atrophic genes, such as those encoding MuRF-1, atrogin-1, and myostatin, and enhanced MHC expression. In addition, dulaglutide treatment inhibited the expression of inflammatory cytokines and apoptotic genes through the induction of heat shock protein 72 (Hsp72) expression via AMPK activation, contributing to the amelioration of disuse-induced muscle atrophy.
GLP-1-based therapies downregulate proinflammatory responses in inflammatoryrelated diseases. This review concludes that GLP-1-based therapy has beneficial effects on inflammatory disease. Thus GLP-1, GLP-1Ragonists, and DPP-4 inhibitors might have important roles as mediators of inflammation
glucagon-like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk.analysis of the effects of GLP-1RAs on bone physiology with special focuses on the mode of action including effects on bone quality, blood flow to bone and on the hormonal regulation of bone metabolism.
OCTOBER: To explore the effects of the glucagon-like peptide 1 (GLP-1) liraglutide on the penile erectile function of rats with diabetic erectile dysfunction (DED) by observing the impact of liraglutide on the expression of eNOS in the corpus cavernosum of diabetic rats.
Methods: We randomly divided 30 six-week-old male SD rats into a normal control (n = 10) and an experimental group (n = 20) , established models of diabetes mellitus (DM) in the experimental rats, and subdivided them into a DM (n = 8) and a GLP-1 group (n = 8) to receive intramuscular injection of normal saline and liraglutide at 5 mg per kg of the body weight per day, respectively. After 12 weeks of intervention, we obtained the levels of FPG, FINS, TG, TC, HDL-C, LDL-C, testosterone, and IL-6 and the indexes of Homa-IR and Homa-β, detected the expressions of Akt/p-Akt and eNOS/p-eNOS in the corpus cavernosum by Western blot, and compared the erectile function between different groups.
Results: The frequency and rate of penile erection were significantly lower in the DM group than in the GLP-1 and normal control groups (P < 0.05) and also lower in the GLP-1 group than in the normal controls (P < 0.05). Immunofluorescence staining showed the expression of eNOS mainly in the cytoplasm of the cavernosal vessels and sinusoidal endothelial cells, markedly lower in the DM and GLP-1 groups than in the normal rats (P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05). The level of eNOS/p-eNOS in the penile tissue was significantly decreased in the DM and GLP-1 groups in comparison with the normal controls (P < 0.01 or P < 0.05), while that of p-eNOS was markedly increased in the GLP-1 group as compared with the DM group (P < 0.05). No statistically significant differences were observed in the Akt level among the three groups of animals (P > 0.05). The expression of p-Akt was remarkably reduced in the DM and GLP-1 groups in comparison with the control rats (P < 0.01 or P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05).
Conclusion: GLP-1 can protect the function of endothelial cells in the corpus cavernosum and improve the erectile function of DED rats by regulating the Akt/ eNOS signaling pathway, which indicates that GLP-1 could be an important option for the treatment and prevention of DED.
Insulin and Insulin Growth Factor-1 (IGF-1) play a major role in body homeostasis and glucose regulation. They also have paracrine/autocrine functions in the brain. The Insulin/IGF-1 signaling pathway contributes to the control of neuronal excitability, nerve cell metabolism and cell survival. Glucagon like peptide-1 (GLP-1), known as an insulinotropic hormone has similar functions and growth like properties as insulin/IGF-1. Growing evidence suggests that dysfunction of these pathways contribute to the progressive loss of neurons in Alzheimer's disease (AD) and Parkinson's disease (PD), the two most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting insulin/IGF-1 and GLP-1 signaling with currently available anti-diabetics. These studies have shown that administration of insulin, IGF-1 and GLP-1 agonists reverses signaling abnormalities and has positive effects on surrogate markers of neurodegeneration and behavioral outcomes. Several proof-of-concept studies are underway that attempt to translate the encouraging preclinical results to patients suffering from AD and PD. In the first part of this review, we discuss physiological functions of insulin/IGF-1 and GLP-1 signaling pathways including downstream targets and receptors distribution within the brain. In the second part, we undertake a comprehensive overview of preclinical studies targeting insulin/IGF-1 or GLP-1 signaling for treating AD and PD. We then detail the design of clinical trials that have used anti-diabetics for treating AD and PD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into treatments for patients with AD and PD.
The peptide hormone glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion and inhibits both gastric emptying and glucagon secretion. GLP-1 receptor (GLP-1R) agonists control glycemia via glucose-dependent mechanisms of action and promote weight loss in obese and diabetic individuals. Nevertheless, the mechanisms and cellular targets transducing the weight loss effects remain unclear. Two recent studies in the JCI provide insight into the neurons responsible for this effect. Sisley et al. reveal that GLP-1R agonist-induced weight loss requires GLP-1Rs in the CNS, while Secher et al. reveal that a small peptide GLP-1R agonist penetrates the brain and activates a subset of GLP-1R-expressing neurons in the arcuate nucleus to produce weight loss. Together, these two studies elucidate pathways that inform strategies coupling GLP-1R signaling to control of body weight in patients with diabetes or obesity.