Insulin
- Introduction
- Function
- Expression
- Interactions and Signalling
- Role in Disease
- Structure
- Gene and Processing
Introduction
Insulin is an important metabolic hormone, regulating blood sugar levels. Recombinant insulin is used to treat diabetes.
Function
Roughly half of secreted insulin is extracted and used by the liver following its entry into the bloodstream.
Insulin is the most potent anabolic hormone known, with multiple synthetic and growth-promoting effects.
Effects on carbohydrate metabolism
- Increases glucose uptake via exocytosis of GLUT-4 stored intracellularly in adipocyte and muscle
- Increases glycogen synthesis and inhibits gluconeogenesis and glycogenolysisin liver
- Increases glucogen synthesis in muscle
- Increases glycolysis through transcriptional and translational upregulation of glucokinase, PFK, and pyruvate kinase
Effects on lipid metabolism
- Decreases TAG degradation by hormone-sensitive lipase in adipose tissues.
- Increases lipoprotein lipase activity, providing FFAs for esterification.
- Increases fatty acid synthesis by increasing the conversion of acetyl CoA to Malonyl CoA.
- Increases TAG synthesis via glucose uptake by adipocytes, which then can produce glycerol 3-phosphate.
- Increases cholesterol synthesis by upregulating HMG Reductase transcription.
- Increases LDL Receptor expression, leading to increased cholesterol uptake
- Decreases ketogenesis
Effects on Protein Metabolism
- increases amino acid uptake
- increases protein synthesis
- decreases proteolysis
Other Effects
- increases ion uptake, especially K+ and PO4-
- is mitogenic, stimulating DNA synthesis and cell growth and differentiation in certain cells
Signaling Pathways
Insulin receptor is a cell surface tyrosine kinase containing two alpha and two beta subunits. MAP kinase signaling pathway activity leads to cell growth, proliferation, and differentiation, while PI3-K pathway activity leads to GLUT-4 expression and lipid, and protein synthesis.
Expression
- produced by beta cells in pancreatic Islets of Langerhans
- stored in cytoplasmic granules and released by exocytosis
- half-life of ~5 minutes; degraded by liver and kidney insulinase
Regulation of Expression
Signals that induce pulsatile insulin expression include:
- increased blood glucose, the most important signal working through GLUT-2
- oral glucose has a greater effect than IV glucose
- amino acids, especially arginine and leucine
- GI hormones such as secretin, glucagon-like peptide 1, and gastric inhibitory peptide
- vagal signaling
- β adrenergic stimulation (ie by isoproterenol)
Signals that inhibit insulin expression include:
- hypoglycemia
- epinephrine and norepinephrine stimulation of α receptors
- stress (ie infection)
Interactions and Signalling
- binds to the alpha subunit of Insulin Receptor, a receptor tyrosine kinase.
- conformational changes activate the beta subunit kinase, which rapidly autophosphorylates itself and induces a signalling cascade that includes phosphorylation of insulin receptor substrate (IRS) proteins
- insulin binding causes receptor internalization and recycling. In situations of elevated insulin levels, the insulin receptor can be downregulated
Role in Disease
Type I diabetes results from a destruction of beta cells and loss of insulin production
Type II diabetes is caused by systemic insulin resistance
Insulin resistance is characterized by a reduction in ability in insulin's target organs - liver, muscle, and fat - to promote glucose use.
Structure
- two strand polypeptide (51 aa) hormone held together by two disulfide bridges
- produced as proinsulin and is cleaved to produce insulin, plus C-peptide, an indicator of insulin secretion in early diabetes
Gene and Processing
- PubMed ref: here
- other info