scholarly journals mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Aleksandra Kezic ◽  
Ljiljana Popovic ◽  
Katarina Lalic
Keyword(s):  
Protein Kinase ◽  
Glucose Metabolism ◽  
Calorie Restriction ◽  
Mtor Inhibitor ◽  
Hepatic Glucose Production ◽  
Mtor Inhibitors ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Solid Organ ◽  
Amp Activated Protein Kinase

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

AMP-activated protein kinase and hepatic genes involved in glucose metabolism

2003 ◽  
Vol 31 (1) ◽  
pp. 220-223 ◽  
Author(s):  
P. Ferré ◽  
D. Azzout-Marniche ◽  
F. Foufelle
Keyword(s):  
Protein Kinase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Snf1 Kinase ◽  
Kinase Activation ◽  
Protein Kinase Activation ◽  
Element Binding Protein ◽  
Amp Activated Protein Kinase

Mammalian AMP-activated protein kinase presents strong structural and functional similarities with the yeast sucrose non-fermenting 1 (Snf1) kinase involved in the derepression of glucose-repressed genes. It is now clearly established that AMP-activated protein kinase in the liver decreases glycolytic/lipogenic gene expression as well as genes involved in hepatic glucose production. This is achieved through a decreased transcriptional efficiency of transcription factors such as sterol-regulatory-element-binding protein-1c, carbohydrate-response-element-binding protein, hepatocyte nuclear factor 4α or forkhead-related protein. Clearly, the long-term consequences of AMP-activated protein kinase activation have to be taken into account if activators of this enzyme are to be designed as anti-diabetic drugs.

Regulation of Hepatic Glucose Production by Transforming Growth Factor Beta 1 via Protein Kinase A

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 2441-PUB ◽  
Author(s):  
QUAN PAN ◽  
YUNMEI CHEN ◽  
HUI YAN ◽  
WANBAO YANG ◽  
ZHENG SHEN ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glucose ◽  
Growth Factor Beta ◽  
Kinase A

scholarly journals Antidiabetic and Antihyperlipidemic Effects ofClitocybe nudaon Glucose Transporter 4 and AMP-Activated Protein Kinase Phosphorylation in High-Fat-Fed Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Mei-Hsing Chen ◽  
Cheng-Hsiu Lin ◽  
Chun-Ching Shih
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transporter ◽  
Body Weight Gain ◽  
Glucose Production ◽  
Hypolipidemic Effect ◽  
Glucose Transporter 4 ◽  
High Fat ◽  
Hepatic Expression ◽  
Amp Activated Protein Kinase

The objective of this study was to evaluate the antihyperlipidemic and antihyperglycemic effects and mechanism of the extract ofClitocybe nuda(CNE), in high-fat- (HF-) fed mice. C57BL/6J was randomly divided into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed with a HF diet for 8 weeks. Then, the HF group was subdivided into five groups and was given orally CNE (including C1: 0.2, C2: 0.5, and C3: 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks. CNE effectively prevented HF-diet-induced increases in the levels of blood glucose, triglyceride, insulin (P<0.001,P<0.01,P<0.05, resp.) and attenuated insulin resistance. By treatment with CNE, body weight gain, weights of white adipose tissue (WAT) and hepatic triacylglycerol content were reduced; moreover, adipocytes in the visceral depots showed a reduction in size. By treatment with CNE, the protein contents of glucose transporter 4 (GLUT4) were significantly increased in C3-treated group in the skeletal muscle. Furthermore, CNE reduces the hepatic expression of glucose-6-phosphatase (G6Pase) and glucose production. CNE significantly increases protein contents of phospho-AMP-activated protein kinase (AMPK) in the skeletal muscle and adipose and liver tissues. Therefore, it is possible that the activation of AMPK by CNE leads to diminished gluconeogenesis in the liver and enhanced glucose uptake in skeletal muscle. It is shown that CNE exhibits hypolipidemic effect in HF-fed mice by increasing ATGL expression, which is known to help triglyceride to hydrolyze. Moreover, antidiabetic properties of CNE occurred as a result of decreased hepatic glucose production via G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic states by CNE in HF-fed mice occurred by regulation of GLUT4, G6Pase, ATGL, and AMPK phosphorylation.

Fenofibrate activates AMP-activated protein kinase and inhibits the expression of gluconeogenesis gene and glucose production in hepatocyte

2008 ◽  
Vol 44 (2) ◽  
pp. 448
Author(s):  
Hisashi Murakami ◽  
Ryuichiro Murakami ◽  
Hiroki Kataoka ◽  
Toru Asai ◽  
Ryotaro Takahashi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Production ◽  
Amp Activated Protein Kinase

scholarly journals Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives

2016 ◽  
Vol 311 (3) ◽  
pp. E620-E627 ◽  
Author(s):  
Tianru Jin ◽  
Jianping Weng
Keyword(s):  
Insulin Resistance ◽  
Degradation Products ◽  
Hepatic Glucose Production ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Beneficial Effects ◽  
Metabolic Functions ◽  
Pathway Activation ◽  
Hepatic Glucose

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed “degradation” products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed “degradation” products of GLP-1 in the liver and elsewhere, including GLP-128–36 and GLP-132–36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation.

scholarly journals Importance of the route of insulin delivery to its control of glucose metabolism

2021 ◽  
Author(s):  
Dale S. Edgerton ◽  
Mary Courtney Moore ◽  
Justin M. Gregory ◽  
Guillaume Kraft ◽  
Alan D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Body ◽  
Whole Body ◽  
Direct Effects ◽  
Pancreatic Insulin ◽  
Hepatic Glucose

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

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