Obesity and Weight Management (2) PDF

11/5/2024 Obesity and Weight Management (2) Dr. Dalia Abu Al- Haijaa Dalia Abu Al-Haija'a 1 1 Obesity: Complications Obesity has a negative independent impact on development and worsening of complications affecting...

11/5/2024 Obesity and Weight Management (2) Dr. Dalia Abu Al- Haijaa Dalia Abu Al-Haija'a 1 1 Obesity: Complications Obesity has a negative independent impact on development and worsening of complications affecting virtually every organ and system. The current course will focus on insulin resistance and its underlying mechanisms (that indeed contribute to the development of several obesity-associated complications even beyond type 2 diabetes, metabolic syndrome and cardiovascular events). Dalia Abu Al-Haija'a 2 2 1  11/5/2024 Dalia Abu Al-Haija'a 3 3 Dalia Abu Al-Haija'a 4 4 2  11/5/2024 1. Insulin Resistance The main physiological actions of insulin in the regulation of nutrient utilization and intermediate metabolism occur in the post-prandial state, when variable rises in plasma glucose trigger insulin secretion. This leads in turn to plasma glucose clearance by stimulating its uptake and utilization by skeletal muscle and adipose tissue, and by blunting hepatic glucose output through inhibition of liver gluconeogenesis and glycogenolysis. Major insulin actions also result in preservation of skeletal muscle mass through inhibition of protein breakdown and translation of specific protein groups, and in induction of lipid storage in adipose tissue. Dalia Abu Al-Haija'a 5 5 1. Insulin Resistance In clinical practice insulin resistance commonly defines reduced insulin action on glucose metabolism. It should conversely be pointed out that individuals defined as insulin resistant for glucose metabolism may present with less impaired or normal insulin action on other important biological targets. Indeed, the presence and time course of changes in insulin effects on protein turnover and lipid metabolic pathways in obese insulin resistant individuals remain largely to be defined and represent relevant questions for basic and clinical research. Dalia Abu Al-Haija'a 6 6 3  11/5/2024 1. Insulin Resistance: Insulin Signaling Pathway Insulin elicits a complex cascade of signaling events, involving multiple nodes. Although we shall present the insulin signaling pathway as a linear chain, it is important to acknowledge the great deal of complexity underlying each node. At most nodes, there are numerous isoforms, which are theoretically capable of responding to and generating subtly different signals. Dalia Abu Al-Haija'a 7 7 Dalia Abu Al-Haija'a 8 8 4  11/5/2024 Dalia Abu Al-Haija'a 9 9 1. Insulin Resistance: Insulin Signaling Pathway Insulin Receptor The insulin receptor binds insulin and triggers a complex cascade of signaling events. The insulin receptor gene encodes a single chain precursor protein which is post-translationally processed into an α- subunit and a β-subunit, which are covalently linked by disulfide bonds. The a-subunit is extracellular and binds insulin, whereas the b-subunit is intracellular and contains a tyrosine kinase domain. Dalia Abu Al-Haija'a 10 10 5  11/5/2024 1. Insulin Resistance: Insulin Signaling Pathway The α/β subunit complexes dimerize with one another to form the insulin receptor. Upon binding insulin, the β-subunits phosphorylate one another and their intracellular substrates. At this signaling node, heterogeneity is generated by alternative splicing and cross-talk with the insulin-like growth factor (IGF)-1 signaling pathway. Alternative splicing of exon 11 yields two isoforms, IRᴬ which lacks the 12 amino acids encoded by this exon and IRᴮ which contains them. The 12 amino acids encoded by exon 11 are contained in the α-subunit and increase the affinity of the receptor for the related growth factor, IGF-2. Dalia Abu Al-Haija'a 11 11 1. Insulin Resistance: Insulin Signaling Pathway In addition, the two isoforms activate different downstream events under certain conditions. The insulin receptor is a member of a subfamily of receptor tyrosine kinases which also includes the IGF-1 receptor and the insulin receptor related receptor (IRR). The α/β subunit complex encoded by the IGF-1 receptor gene not only dimerizes with itself to form the IGF receptor, but also dimerizes with the α/β subunit complex of the insulin receptor to generate hybrid receptors. The insulin receptor, IGF receptor and hybrid receptor all bind insulin and IGF-1 with varying affinities. Dalia Abu Al-Haija'a 12 12 6  11/5/2024 1. Insulin Resistance: Insulin Signaling Pathway Although there is a great deal of overlap between insulin and IGF signaling, insulin tends to regulate metabolism whereas IGF tends to regulate growth and proliferation. Hyperinsulinemia in the metabolic syndrome could potentially lead to the activation of the hybrid receptor or IGF receptor, driving cell growth and proliferation. This has been implicated in the pathogenesis of acanthosis nigricans, the thickening of the skin, particularly in the neck and axilla, present in insulin resistant individuals, the increased risk of cancer in patients with the metabolic syndrome, pseudo-acromegaly and PCOS. However, other factors, including changes in the IGF binding proteins which alter IGF activity, could also play a role in these processes. Dalia Abu Al-Haija'a 13 13 Dalia Abu Al-Haija'a 14 14 7  11/5/2024 Acanthosis nigricans Insulin resistance and pseudoacromegaly Dalia Abu Al-Haija'a 15 15 Dalia Abu Al-Haija'a 16 16 8  11/5/2024 1. Insulin Resistance: Molecular Mechanisms of Insulin Resistance Abnormalities of insulin signaling account for insulin resistance Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). The binding of insulin to the α subunit of its receptor activates the tyrosine kinase of the β subunit of the receptor, leading to autophosphorylation, as well as tyrosine phosphorylation of several IR substrates (IRS), including IRS-1 and IRS-2. Dalia Abu Al-Haija'a 17 17 1. Insulin Resistance: Molecular Mechanisms of Insulin Resistance These, in turn, interact with phosphatidylinositol 3-kinase (PI3K). Activation of PI3K stimulates the main downstream effector Akt, a serine/threonine kinase, which stimulates the glucose uptake through the translocation of the major glucose transporter GLUT-4 to the plasma membrane. Abnormalities of the IR function that may contribute to insulin resistance include the defects of receptor structure, number, binding affinity, and/ or its signaling capacity. It is noteworthy that hyperglycemia, accounts for the development of insulin resistance through the generation of reactive oxygen species (ROS), which abrogate insulin-induced tyrosine autophosphorylation of IR. Dalia Abu Al-Haija'a 18 18 9  11/5/2024 1. Insulin Resistance: Molecular Mechanisms of Insulin Resistance In addition, several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IRS proteins, including proteasome-mediated degradation, , phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. Phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of PI3-K, inhibiting further signaling. In addition, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation, also impairing insulin signaling. Dalia Abu Al-Haija'a 19 19 1. Insulin Resistance: Molecular Mechanisms of Insulin Resistance The mechanistic role of abnormalities of IR or IRS-1 signaling in the pathogenesis of insulin resistance is supported by several pioneering studies performed in genetically engineered mice. Transgenic mice with targeted disruption of the IRS-1 gene, exhibited higher BP and plasma triglyceride levels compared to wildtype mice. They also showed impairment of endothelium dependent vascular relaxation. It is noteworthy that IR defects are tissue-specific and depends upon the type of stress; therefore, the insulin resistance phenomenon can be localized in specific tissues and does not necessarily associate with metabolic abnormalities. Dalia Abu Al-Haija'a 20 20 10