Obesity: Multisystem Complications and Insulin Resistance

Obesity negatively affects many organs and systems, worsening related complications.

Reduced effectiveness of insulin in regulating glucose metabolism.

Insulin boosts glucose uptake, reduces liver glucose production, and encourages fat storage.

Insulin prevents muscle breakdown and promotes protein synthesis.

Reduced insulin action primarily on glucose metabolism.

How insulin affects protein turnover and fat metabolism in obesity is not fully understood.

Glucose in the blood.

Processes in the liver that release glucose into the blood.

A protein that binds insulin, triggering a cascade of signaling events.

Composed of an alpha (extracellular) and beta (intracellular) subunit, linked by disulfide bonds. The beta subunit has a tyrosine kinase domain.

Insulin binding causes beta subunits to phosphorylate each other and their intracellular substrates.

A complex series of events triggered by insulin binding to its receptor, leading to cellular responses.

Alternative splicing and cross-talk with other pathways (e.g., IGF-1) create variations in the insulin signaling response.

Insulin receptor subunits pair up to form the functional receptor complex.

Different versions (isoforms) of the insulin receptor are created by splicing different parts of the gene.

Different forms of the insulin receptor due to alternative splicing (e.g., with and without exon 11).

A transmembrane protein that detects insulin and triggers a signaling cascade.

The process by which insulin triggers cellular responses, primarily glucose uptake.

The process of transporting glucose into cells.

A glucose transporter protein that moves glucose into cells.

The addition of a phosphate group to a tyrosine amino acid.

High blood sugar levels.

Molecules that can harm cells.

Exon 11 encodes 12 amino acids in the α-subunit, increasing the receptor's binding strength for IGF-2.

A group of receptor tyrosine kinases that includes the insulin receptor, IGF-1 receptor, and insulin receptor-related receptor (IRR).

Receptors formed by the dimerization of insulin receptor and IGF-1 receptor subunits.

Insulin primarily manages metabolism, while IGF focuses on growth and cell division.

High levels of insulin in the blood.

Thickening of the skin, often seen in insulin-resistant individuals.

A group of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.

Proteins that regulate IGF activity by binding to it.

Insulin resistance is characterized by reduced insulin signaling. This occurs when the insulin receptor (IR) and its substrate (IRS) proteins are hindered from activating downstream signaling pathways, effectively preventing glucose uptake and utilization.

Phosphorylation of IRS-1 at serine 612 leads to the separation of the p85 subunit from PI3-kinase. This disrupts insulin signaling, ultimately decreasing glucose uptake.

Phosphorylation of IRS-1 at serine 307 causes its detachment from the insulin receptor (IR) and triggers its breakdown by the proteasome. This hinders insulin signaling and impairs glucose regulation.

Insulin resistance is not a uniform phenomenon across all tissues. Different tissues can exhibit varying degrees of insulin resistance due to distinct stressors and mechanisms. This localized resistance doesn't necessarily imply overall metabolic abnormalities.