Molecular Mechanisms of Brain Insulin Signaling 1
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
The insulin signaling pathway is a tightly regulated molecular mechanism that controls a range of metabolically important functions in cells and generally induces energy-consuming processes, such as protein synthesis, growth, and proliferation. Moreover, it also controls both peripheral metabolic functions (e.g., glucose uptake or hepatic glucose production), as well as central metabolic functions (e.g., control of appetite and thus food intake). As such, a hyperactivation could lead to detrimental metabolic outcomes. To counteract the hyperactivation of the insulin response, the signaling pathway is subjected to a variety of negative feedback modulations on most of its protein components via posttranslational modifications, transcriptional control, and targeted protein degradation. However, if these feedback loops are continually activated, a chronic insulin-resistant state can occur.
Insulin Resistance
Jack L. Leahy, Nathaniel G. Clark, William T. Cefalu in Medical Management of Diabetes Mellitus, 2000
The explanation provided for insulin's effect on glucose uptake is less well defined, but involves the enzyme phosphatidylinositide-3 kinase (Pl-3 kinase). Insulin stimulation increases the amount of Pl-3 kinase associated with IRS, and its activity is directly activated by docking. Activation of the Pl-3 kinase appears to be critical for transducing the metabolic effects of insulin, as inhibition of Pl- 3 kinase activation blocks insulin's ability to stimulate glucose transport. However, other growth factor receptors activate Pl-3 kinase to the same extent as the insulin receptor, but they do not stimulate glucose transport. Therefore, it appears that although Pl-3 kinase is necessary for the action of insulin, it is not sufficient, in and of itself, to account for the glucose uptake process. The additional factors that are responsible for the stimulation of glucose transport are still unknown. In summary, current evidence suggests that IRS proteins, in their phosphorylated form, may regulate insulin signaling by acting as a docking site by binding to and regulating intracellular enzymes containing SH2 domains that allow the insulin signal to "diverge" throughout the target cell.
Insulinotropic and Muscle Protein Synthetic Effects of Branched-Chain Amino Acids
Chad Cox in Clinical Nutrition and Aging, 2017
These potential positive effects of BCAA supplementation for metabolic health and aging must be balanced against any negative outcomes. In this regard, recent human studies have found potential links between elevated plasma BCAA and obesity/type 2 diabetes. Using metabolomics profiling, Newgard and colleagues [95] demonstrated that BCAA were elevated in obese humans, and suggested that BCAA overload may contribute to insulin resistance. In a separate study, circulating BCAA (along with phenylalanine and tyrosine) demonstrated high associations with the development of type 2 diabetes in a group of 2422 individuals who had blood samples taken at baseline and were followed for 12 years [96]. It has been proposed that elevated BCAA concentrations result in an over-activation of mTOR/p70S6 kinase which, in turn, results in an increased IRS-1 phosphorylation on serine residues thereby inhibiting PI3 kinase [94]. This inhibition of PI3K in turn leads to impaired insulin signaling and contributes to insulin resistance [97,98,99]. Future studies are needed to decipher whether these findings are (i) indicative of BCAA contributing to impaired metabolic health, (ii) the result of impaired BCAA catabolism in obesity/diabetes, or (iii) are a possible compensatory mechanism in response to obesity.
The effect of tramadol on blood glucose concentrations: a systematic review
Published in Expert Review of Clinical Pharmacology, 2020
Samaneh Nakhaee, Jeffrey Brent, Christopher Hoyte, Khadijeh Farrokhfall, Farshad M Shirazi, Masoumeh Askari, Omid Mehrpour
Tramadol is an analgesic that has diverse pharmacological actions and a concomitant capability for numerous adverse effects. Blood glucose impairments, especially hypoglycemia, should be regarded as one of the consequential side effects of tramadol. Studies conducted on diabetic subjects universally reported hypoglycemia. Tramadol-induced hypoglycemia may be severe in some cases. Based on the results of this study, glycemic changes, particularly hypoglycemia, should be considered a potential side effect of tramadol use. Mechanisms of hypoglycemia due to tramadol may include 1. Activation of pancreatic opioid receptors. 2. Increased hepatic insulin sensitivity 3. A decrease in the liver’s expression of lPEPCK. 4. Activation of the insulin signaling pathway. 5. Increasing insulin receptor expression. 6. Activation of serotonin-induced increase in insulin concentrations. 7. The release of beta-endorphin. 8. Stimulation of glucose uptake by muscles. 9. Activation of peripheral opioid µ-receptors, which can increase glucose uptake. Very few studies evaluated tramadol-induced hyperglycemia, nor have they studied any possible tramadol dose effect. Therefore, conclusions regarding hyperglycemias should be regarded as speculative.
Alpha-Mangosteen lessens high-fat/high-glucose diet and low-dose streptozotocin induced-hepatic manifestations in the insulin resistance rat model
Published in Pharmaceutical Biology, 2023
Vivian Soetikno, Prisma Andini, Miskiyah Iskandar, Clark Christensen Matheos, Joshua Alward Herdiman, Iqbal Kevin Kyle, Muhammad Nur Imaduddin Suma, Melva Louisa, Ari Estuningtyas
Next, we evaluated the insulin signalling pathway and its relationship to AMPK. A previous study has shown that insulin signalling and AMPK show vital roles in balancing intracellular energy levels and glucose uptake, in which both pathways stimulate energy conservation and survival of muscle exposed to severe glucose deprivation (Chopra et al. 2012). It has been demonstrated that insulin signaling is mediated by IRS protein. IRS1 is the most common and widely expressed in many tissues including the liver. Metabolic effects of insulin downstream of IRS proteins are mediated by the PI3K (Gallagher et al. 2012). In the present study, HF/HG/STZ administration was able to downregulate the level of IRS1 and PI3K as compared to that of normal rats, while the administration of α-MG at both doses and metformin showed an increase in IRS1 and PI3K. This result is consistent with evidence that α-MG activates insulin signalling and protects pancreatic β-cells against STZ-induced apoptotic damage (Lee et al. 2018).
ASK1 and its role in cardiovascular and other disorders: available treatments and future prospects
Published in Expert Review of Proteomics, 2019
Mohammad Hassan Baig, Abu Baker, Ghulam M Ashraf, Jae-June Dong
A large number of studies have provided pieces of evidence regarding the association of ASK1 with the pathogenesis of diabetes. Insulin receptor substrate 1 (IRS-1), which is one of the key mediators in insulin signaling has been well reported to be negatively regulated by ASK1 [168]. It has been found through JNK-mediated IRS-1 phosphorylation, ASK1 negatively regulates IRS-1 [169]. TNF-α is one of the important factors responsible for aggravating insulin resistance [170]. In mitochondria, the TNF-α-stimulated ROS production triggers ASK1, which in turn activates JNK and this activation of JNK leads to IRS-1 serine phosphorylation [12,169]. IRS-1 serine phosphorylation is a very crucial factor for insulin resistance, which results in type 2 diabetes. The studies on Atika mice shows that the genetic deletion of ASK1 ameliorated pancreatic β cell death, which resulted in delaying the onset of diabetes [171]. These findings show that the inhibition of ASK1 may be an effective therapy for the treatment of diabetes [171].
Related Knowledge Centers
- Adipocyte
- Glucose
- Metabolic Pathway
- Liver
- Gluconeogenesis
- Insulin
- Carbohydrate
- Muscle Cell
- Blood Sugar Regulation
- Hormone